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Abstract:

The present invention relates to tetraline and indane derivatives of the
formula (I)
##STR00001##
or a physiologically tolerated salt thereof.
The invention relates to pharmaceutical compositions comprising such
tetraline and indane derivatives, and the use of such tetraline and
indane derivatives for therapeutic purposes. The tetraline and indane
derivatives are GlyT1 inhibitors.

17. Compound as claimed in claim 1, wherein A is a benzene ring; R is
R1--W-A1-Q-Y-A2X1; R1 is C1-C6-alkyl,
C3-C12-cycloalkyl-C1-C4-alkyl,
C3-C12-cycloalkyl, or optionally substituted
C3-C12-heterocyclyl; W is a bond; A1 is a bond; Q is
--S(O)2--; Y is --NR9 or a bond; A2 is
C1-C4-alkylene or a bond; X1 is --O-- or
C1-C4-alkylene; R2 is hydrogen or halogen; R3 is
hydrogen; Y1 is optionally substituted C1-C4-alkylene;
R4a is hydrogen, C1-C6-alkyl, C3-C12-cycloalkyl
or C3-C12-heterocyclyl; or R4a is optionally substituted
C1-C4-alkylene that is bound to a carbon atom in Y1;
R4b is hydrogen; or R4a, R4b, together are
C1-C6-alkylene, wherein one --CH2-- of
C1-C4-alkylene may be replaced by an oxygen atom; X2 is
CR12aR12b; X3 is a bond; R5 is optionally substituted
phenyl; n is 0 or 1; R9 is hydrogen; or R9 is
C1-C4-alkylene that is bound to a carbon atom in X1 and
X1 is C1-C4-alkylene; R12a is hydrogen; and R12b
is hydrogen; or R12a, R12b together are
C1-C4-alkylene.

19. Pharmaceutical composition which comprises a carrier and a compound
of claim 1.

20. A method for treating a neurologic or psychiatric disorder or pain in
a mammalian patient in need thereof which comprises administering to the
patient a therapeutically effective amount of a compound of claim 1.

Description:

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This claims priority to U.S. Provisional Patent Application No.
61/373,654, filed on Aug. 13, 2010, the contents of which are hereby
incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to tetraline and indane derivatives,
pharmaceutical compositions comprising such tetraline and indane
derivatives, and the use of such tetraline and indane derivatives for
therapeutic purposes. The tetraline and indane derivatives are GlyT1
inhibitors.

[0003] Dysfunction of glutamatergic pathways has been implicated in a
number of disease states in the human central nervous system (CNS)
including but not limited to schizophrenia, cognitive deficits, dementia,
Parkinson disease, Alzheimer disease and bipolar disorder. A large number
of studies in animal models lend support to the NMDA hypofunction
hypothesis of schizophrenia.

[0004] NMDA receptor function can be modulated by altering the
availability of the co-agonist glycine. This approach has the critical
advantage of maintaining activity-dependent activation of the NMDA
receptor because an increase in the synaptic concentration of glycine
will not produce an activation of NMDA receptors in the absence of
glutamate. Since synaptic glutamate levels are tightly maintained by high
affinity transport mechanisms, an increased activation of the glycine
site will only enhance the NMDA component of activated synapses.

[0005] Two specific glycine transporters, GlyT1 and GlyT2 have been
identified and shown to belong to the Na/Cl-dependent family of
neurotransmitter transporters which includes taurine, gamma-aminobutyric
acid (GABA), proline, monoamines and orphan transporters. GlyT1 and GlyT2
have been isolated from different species and shown to have only 50%
identity at the amino acid level. They also have a different pattern of
expression in mammalian central nervous system, with GlyT2 being
expressed in spinal cord, brainstem and cerebellum and GlyT1 present in
these regions as well as forebrain areas such as cortex, hippocampus,
septum and thalamus. At the cellular level, GlyT2 has been reported to be
expressed by glycinergic nerve endings in rat spinal cord whereas GlyT1
appears to be preferentially expressed by glial cells. These expression
studies have led to the suggestion that GlyT2 is predominantly
responsible for glycine uptake at glycinergic synapses whereas GlyT1 is
involved in monitoring glycine concentration in the vicinity of NMDA
receptor expressing synapses. Recent functional studies in rat have shown
that blockade of GlyT1 with the potent inhibitor
(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])-sarcosine (NFPS)
potentiates NMDA receptor activity and NMDA receptor-dependent long-term
potentiation in rat.

[0006] Molecular cloning has further revealed the existence of three
variants of GlyT1, termed GlyT-1a, GlyT-1b and GlyT-1c, each of which
displays a unique distribution in the brain and peripheral tissues. The
variants arise by differential splicing and exon usage, and differ in
their N-terminal regions.

[0007] The physiological effects of GlyT1 in forebrain regions together
with clinical reports showing the beneficial effects of GlyT1 inhibitor
sarcosine in improving symptoms in schizophrenia patients suggest that
selective GlyT1 inhibitors represent a new class of antipsychotic drugs.

[0008] Glycine transporter inhibitors are already known in the art, for
example:

[0055] According to a second aspect, the present invention relates to
tetraline and indane derivatives of the formula (I) or a physiologically
tolerated salt thereof, wherein the Y1 is a bond, R4a is
cycloalkyl and A, R1, W, A1, Q, Y, A2, R2, R3,
R4b, X2, X3, R5, n are as defined herein, provided
that the tetraline and indane derivative is not propane-1-sulfonic acid
(8-benzyl-7-cyclopropylamino-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-am-
ide or a physiologically tolerated salt thereof such as the hydrochloride.
[0056] Thus, the present invention relates to tetraline and indane
derivatives having the formula (Ia)

[0058] Thus, the term tetraline and indane derivative is used herein to
denote in particular tetralines (n=1) and fused cyclohexanes (n=1)
wherein the benzene ring is replaced by a 5- or 6-membered heterocyclic
ring as well as homologous bicyclic compounds wherein n is 0 or 2.

[0059] Said compounds of formula (I), i.e., the tetraline and indane
derivatives of formula (I) and their physiologically tolerated salts, are
glycine transporter inhibitors and thus useful as pharmaceuticals.

[0060] The present invention thus further relates to the compounds of
formula (I) for use in therapy.

[0061] The present invention also relates to pharmaceutical compositions
which comprise a carrier and a compound of formula (I).

[0062] In particular, said compounds, i.e., the tetraline and indane
derivatives and their physiologically tolerated salts, are inhibitors of
the glycine transporter GlyT1.

[0063] The present invention thus further relates to the compounds of
formula (I) for use in inhibiting the glycine transporter.

[0064] The present invention also relates to the use of the compounds of
formula (I) in the manufacture of a medicament for inhibiting the glycine
transporter GlyT1 and corresponding methods of inhibiting the glycine
transporter GlyT1.

[0065] Glycine transport inhibitors and in particular inhibitors of the
glycine transporter GlyT1 are known to be useful in treating a variety of
neurologic and psychiatric disorders.

[0066] The present invention thus further relates to the compounds of
formula (I) for use in treating a neurologic or psychiatric disorder.

[0067] The present invention further relates to the compounds of formula
(I) for use in treating pain.

[0068] The present invention also relates to the use of the compounds of
formula (I) in the manufacture of a medicament for treating a neurologic
or psychiatric disorder and corresponding methods of treating said
disorders. The present invention also relates to the use of the compounds
of formula (I) in the manufacture of a medicament for treating pain and
corresponding methods of treating pain.

[0069] The present invention further relates to tetraline and indane
derivatives of formula (II)

[0070] The tetraline and indane derivatives of formula (II) are useful as
intermediates in the preparation of GlyT1 inhibitors, in particular those
of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

[0071] Provided that the tetraline and indane derivatives of the formula
(I) or (II) of a given constitution may exist in different spatial
arrangements, for example if they possess one or more centers of
asymmetry, polysubstituted rings or double bonds, or as different
tautomers, it is also possible to use enantiomeric mixtures, in
particular racemates, diastereomeric mixtures and tautomeric mixtures,
preferably, however, the respective essentially pure enantiomers,
diastereomers and tautomers of the compounds of formula (I) or (II)
and/or of their salts.

[0072] According to one embodiment, an enantiomer of the compounds of the
present invention has the following formula:

[0077] The present invention moreover relates to compounds of formula (I)
or (II) as defined herein, wherein at least one of the atoms has been
replaced by its stable, non-radioactive isotope (e.g., hydrogen by
deuterium, 12C by 13C, 14N by 15N, 16O by
18O) and preferably wherein at least one hydrogen atom has been
replaced by a deuterium atom.

[0078] Of course, such compounds contain more of the respective isotope
than this naturally occurs and thus is anyway present in the compounds
(I) or (II).

[0079] Stable isotopes (e.g., deuterium, 13O, 15N, 18O) are
nonradioactive isotopes which contain one or more additional neutron than
the normally abundant isotope of the respective atom. Deuterated
compounds have been used in pharmaceutical research to investigate the in
vivo metabolic fate of the compounds by evaluation of the mechanism of
action and metabolic pathway of the non-deuterated parent compound (Blake
et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are
important in the design of safe, effective therapeutic drugs, either
because the in vivo active compound administered to the patient or
because the metabolites produced from the parent compound prove to be
toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14,
pp. 2-36, Academic Press, London, 1985; Kato et al., J. Labelled Comp.
Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol.
Pharmacol., 77, 79-88 (1999).

[0080] Incorporation of a heavy atom particularly substitution of
deuterium for hydrogen, can give rise to an isotope effect that could
alter the pharmacokinetics of the drug. This effect is usually
insignificant if the label is placed at a metabolically inert position of
the molecule.

[0081] Stable isotope labeling of a drug can alter its physico-chemical
properties such as pKa and lipid solubility. These changes may influence
the fate of the drug at different steps along its passage through the
body. Absorption, distribution, metabolism or excretion can be changed.
Absorption and distribution are processes that depend primarily on the
molecular size and the lipophilicity of the substance. These effects and
alterations can affect the pharmacodynamic response of the drug molecule
if the isotopic substitution affects a region involved in a
ligand-receptor interaction.

[0082] Drug metabolism can give rise to large isotopic effect if the
breaking of a chemical bond to a deuterium atom is the rate limiting step
in the process. While some of the physical properties of a stable
isotope-labeled molecule are different from those of the unlabeled one,
the chemical and biological properties are the same, with one important
exception: because of the increased mass of the heavy isotope, any bond
involving the heavy isotope and another atom will be stronger than the
same bond between the light isotope and that atom. In any reaction in
which the breaking of this bond is the rate limiting step, the reaction
will proceed slower for the molecule with the heavy isotope due to
"kinetic isotope effect". A reaction involving breaking a C-D bond can be
up to 700 percent slower than a similar reaction involving breaking a
C--H bond. If the C-D bond is not involved in any of the steps leading to
the metabolite, there may not be any effect to alter the behavior of the
drug. If a deuterium is placed at a site involved in the metabolism of a
drug, an isotope effect will be observed only if breaking of the C-D bond
is the rate limiting step. There is evidence to suggest that whenever
cleavage of an aliphatic C--H bond occurs, usually by oxidation catalyzed
by a mixed-function oxidase, replacement of the hydrogen by deuterium
will lead to observable isotope effect. It is also important to
understand that the incorporation of deuterium at the site of metabolism
slows its rate to the point where another metabolite produced by attack
at a carbon atom not substituted by deuterium becomes the major pathway a
process called "metabolic switching".

[0084] The weight percentage of hydrogen in a mammal (approximately 9%)
and natural abundance of deuterium (approximately 0.015%) indicates that
a 70 kg human normally contains nearly a gram of deuterium. Furthermore,
replacement of up to about 15% of normal hydrogen with deuterium has been
effected and maintained for a period of days to weeks in mammals,
including rodents and dogs, with minimal observed adverse effects (Czajka
D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann.
New York Acad. Sci. 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961
201: 357). Higher deuterium concentrations, usually in excess of 20%, can
be toxic in animals. However, acute replacement of as high as 15%-23% of
the hydrogen in humans' fluids with deuterium was found not to cause
toxicity (Blagojevic N et al. in "Dosimetry & Treatment Planning for
Neutron Capture Therapy", Zamenhof R, Solares G and Harling 0 Eds. 1994.
Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab.
23: 251 (1997)).

[0086] The hydrogens present on a particular organic compound have
different capacities for exchange with deuterium. Certain hydrogen atoms
are easily exchangeable under physiological conditions and, if replaced
by deuterium atoms, it is expected that they will readily exchange for
protons after administration to a patient. Certain hydrogen atoms may be
exchanged for deuterium atoms by the action of a deuteric acid such as
D2SO4/D2O. Alternatively, deuterium atoms may be
incorporated in various combinations during the synthesis of compounds of
the invention. Certain hydrogen atoms are not easily exchangeable for
deuterium atoms. However, deuterium atoms at the remaining positions may
be incorporated by the use of deuterated starting materials or
intermediates during the construction of compounds of the invention.

[0088] The organic moieties mentioned in the above definitions of the
variables are--like the term halogen--collective terms for individual
listings of the individual group members. The prefix Cn--Cm
indicates in each case the possible number of carbon atoms in the group.

[0090] The term halogen denotes in each case fluorine, bromine, chlorine
or iodine, in particular fluorine or chlorine.

[0091] C1-C4-Alkyl is a straight-chain or branched alkyl group
having from 1 to 4 carbon atoms. Examples of an alkyl group are methyl,
C2-C4-alkyl such as ethyl, n-propyl, iso-propyl, n-butyl,
2-butyl, iso-butyl or tert-butyl. C1-C2-Alkyl is methyl or
ethyl, C1-C3-alkyl is additionally n-propyl or isopropyl.

[0094] C6-C12-Aryl-C1-C4-alkyl is a straight-chain or
branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon
atoms, more preferably 1 or 2 carbon atoms, in particular 1 or two carbon
atoms, wherein one hydrogen atom is replaced by C6-C12-aryl,
such as in benzyl.

[0095] Hydroxy-C1-C4-alkyl is a straight-chain or branched alkyl
group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more
preferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms are
replaced by one or two hydroxyl groups, such as in hydroxymethyl,
(R)-1-hydroxyethyl, (S)-1-hydroxyethyl, 2-hydroxyethyl,
(R)-1-hydroxypropyl, (S)-1-hydroxypropyl, 2-hydroxypropyl,
3-hydroxypropyl, (R)-2-hydroxy-1-methylethyl,
(S)-2-hydroxy-1-methylethyl, 2-hydroxy-1-(hydroxymethyl)ethyl,
(R)-1-hydroxybutyl, (S)-1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl,
4-hydroxybutyl.

[0097] Amino-C1-C4-alkyl is a straight-chain or branched alkyl
group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more
preferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,
wherein one hydrogen atom is replaced by an amino group, such as in
aminomethyl, 2-aminoethyl.

[0098] C1-C6-Alkylamino-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a C1-C6-alkylamino group, in particular by a
C1-C4-alkylamino group, such as in methylaminomethyl,
ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl,
n-butylaminomethyl, 2-butylaminomethyl, iso-butylaminomethyl or
tert-butylaminomethyl.

[0099] Di-C1-C6-Alkylamino-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a di-C1-C6-Alkylamino group, in particular by a
di-C1-C4-alkylamino group, such as in dimethylaminomethyl.

[0100] C1-C6-Alkylcarbonylamino-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a C1-C6-alkylcarbonylamino group, in particular by a
C1-C4-alkylcarbonylamino group, such as in
methylcarbonylaminomethyl, ethylcarbonylaminomethyl,
n-propylcarbonylaminomethyl, iso-propylcarbonylaminomethyl,
n-butylcarbonylaminomethyl, 2-butylcarbonylaminomethyl,
iso-butylcarbonylaminomethyl or tertbutylcarbonylaminomethyl.

[0101] C1-C6-Alkylaminocarbonylamino-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a C1-C6-alkylaminocarbonylamino group, in particular by a
C1-C4-alkylaminocarbonylamino group, such as in
methylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl,
n-propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl,
n-butylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl,
isobutylaminocarbonylaminomethyl or tert-butylaminocarbonylaminomethyl.

[0102] Di-C1-C6-alkylaminocarbonylamino-C1-C4-alkyl is
a straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a di-C1-C6-alkylaminocarbonylamino group, in particular by a
di-C1-C4-alkylaminocarbonylamino group, such as in
dimethylaminocarbonylaminomethyl, dimethylaminocarbonyl-aminoethyl,
dimethylaminocarbonylaminon-propyl.

[0103] C1-C6-Alkylsulfonylamino-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by a C1-C6-alkylsulfonylamino group, in particular by a
C1-C4-alkylsulfonylamino group, such as in
methylsulfonylaminomethyl, ethylsulfonylaminomethyl,
n-propylsulfonylaminomethyl, isopropylsulfonylaminomethyl,
n-butylsulfonylaminomethyl, 2-butylsulfonylaminomethyl,
isobutylsulfonylaminomethyl or tert-butylsulfonylaminomethyl.

[0104] (C6-C12-Aryl-C1-C6-alkyl)amino-C1-C4
alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon
atoms, preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon
atoms, in particular 1 or two carbon atoms, wherein one hydrogen atom is
replaced by a (C6-C12-aryl-C1-C6-alkyl)amino group,
in particular a (C6-C12-aryl-C1-C2-alkyl)amino group,
such as in benzylaminomethyl.

[0105] C3-C12-Heterocyclyl-C1-C4-alkyl is a
straight-chain or branched alkyl group having 1 to 4 carbon atoms,
preferably 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms, in
particular 1 or two carbon atoms, wherein one hydrogen atom is replaced
by C3-C12-heterocyclyl, such as in N-pyrrolidinylmethyl,
N-piperidinylmethyl, N-morpholinylmethyl.

[0106] C3-C12-Cycloalkyl is a cycloaliphatic radical having from
3 to 12 carbon atoms. In particular, 3 to 6 carbon atoms form the cyclic
structure, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The cyclic structure may be unsubstituted or may carry 1, 2, 3 or 4
C1-C4 alkyl radicals, preferably one or more methyl radicals.

[0107] Carbonyl is >C═O.

[0108] C1-C6-Alkylcarbonyl is a radical of the formula
R--C(O)--, wherein R is an alkyl radical having from 1 to 6, preferably
from 1 to 4, in particular 1 or 2 carbon atoms as defined herein.
Examples include acetyl, propionyl, n-butyryl, 2-methylpropionyl,
pivaloyl.

[0109] Halogenated C1-C6-alkylcarbonyl is
C1-C6-alkylcarbonyl as defined herein, wherein at least one,
e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4
or a corresponding number of identical or different halogen atoms.
Examples include fluoromethylcarbonyl, difluoromethylcarbonyl,
trifluoromethylcarbonyl. Further examples are
1,1,1-trifluoroeth-2-ylcarbonyl, 1,1,1-trifluoroprop-3-ylcarbonyl.

[0110] C6-C12-Arylcarbonyl is a radical of the formula
R--C(O)--, wherein R is an aryl radical having from 6 to 12 carbon atoms
as defined herein. Examples include benzoyl.

[0111] C1-C6-Alkoxycarbonyl is a radical of the formula
R--O--C(O)--, wherein R is an alkyl radical having from 1 to 6,
preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined
herein. Examples include methoxycarbonyl and tert-butyloxycarbonyl.

[0112] Halogenated C1-C6-alkoxycarbonyl is a
C1-C6-alkoxycarbonyl as defined herein, wherein at least one,
e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4
or a corresponding number of identical or different halogen atoms.

[0113] C6-C12-Aryloxycarbonyl is a radical of the formula
R--O--C(O)--, wherein R is an aryl radical having from 6 to 12 carbon
atoms as defined herein. Examples include phenoxycarbonyl.

[0114] Cyano is --C≡N.

[0115] Aminocarbonyl is NH2C(O)--.

[0116] C1-C6-Alkylaminocarbonyl is a radical of the formula
R--NH--C(O)--, wherein R is an alkyl radical having from 1 to 6,
preferably from 1 to 4, in particular 1 or 2 carbon atoms as defined
herein. Examples include methylaminocarbonyl.

[0117] (Halogenated C1-C4-alkyl)aminocarbonyl is a
C1-C4-alkylaminocarbonyl as defined herein, wherein at least
one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2,
3, 4 or a corresponding number of identical or different hydrogen atoms.

[0118] C6-C12-Arylaminocarbonyl is a radical of the formula
R--NH--C(O)--, wherein R is an aryl radical having from 6 to 12 carbon
atoms as defined herein. Examples include phenylaminocarbonyl.

[0129] C1-C6-Hydroxyalkoxy is an alkoxy radical having from 1 to
6, preferably from 1 to 4 carbon atoms as defined herein, wherein one or
two hydrogen atoms are replaced by hydroxy. Examples include
2-hydroxyethoxy, 3-hydroxypropoxy, 2-hydroxypropoxy,
1-methyl-2-hydroxyethoxy and the like.

[0130] C1-C6-Alkoxy-C1-C4-alkoxy is an alkoxy radical
having from 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms as
defined herein, wherein one or two hydrogen atoms are replaced by one or
two alkoxy radicals having from 1 to 6, preferably from 1 to 4 carbon
atoms as defined herein. Examples include methoxymethoxy,
2-methoxyethoxy, 1-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy,
1-methyl-1-methoxyethoxy, ethoxymethoxy, 2-ethoxyethoxy, 1-ethoxyethoxy,
3-ethoxypropoxy, 2-ethoxypropoxy, 1-methyl-1-ethoxyethoxy and the like.

[0131] Amino-C1-C4-alkoxy is an alkoxy radical having from 1 to
4, preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogen
atom is replaced by an amino group. Examples include 2-aminoethoxy.

[0132] C1-C6-Alkylamino-C1-C4-alkoxy is an alkoxy
radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined
herein, wherein one hydrogen atom is replaced by an alkylamino group
having from 1 to 6, preferably from 1 to 4 carbon atoms as defined
herein. Examples include methylaminomethoxy, ethylaminomethoxy,
n-propylaminomethoxy, isopropylaminomethoxy, n-butylaminomethoxy,
2-butylaminomethoxy, isobutylaminomethoxy, tert-butylaminomethoxy,
2-(methylamino)ethoxy, 2-(ethylamino)ethoxy, 2-(n-propylamino)ethoxy,
2-(iso-propylamino)ethoxy, 2-(n-butylamino)ethoxy,
2-(2-butylamino)ethoxy, 2-(iso-butylamino)ethoxy,
2-(tert-butylamino)ethoxy.

[0133] Di-C1-C6-alkylamino-C1-C4-alkoxy is an alkoxy
radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined
herein, wherein one hydrogen atom is replaced by a dialkylamino group
having from 1 to 6, preferably from 1 to 4 carbon atoms as defined
herein. Examples include dimethylaminomethoxy, diethylaminomethoxy,
N-methyl-N-ethylamino)ethoxy, 2-(dimethylamino)ethoxy,
2-(diethylamino)ethoxy, 2-(N-methyl-N-ethylamino)ethoxy.

[0134] C1-C6-Alkylcarbonylamino-C1-C4-alkoxy is an
alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as
defined herein, wherein one hydrogen atom is replaced by an
alkylcarbonylamino group wherein the alkyl group has from 1 to 6,
preferably from 1 to 4 carbon atoms as defined herein. Examples include
methylcarbonylaminomethoxy, ethylcarbonylaminomethoxy,
n-propylcarbonylaminomethoxy, isopropylcarbonylaminomethoxy,
n-butylcarbonylaminomethoxy, 2-butylcarbonylaminomethoxy,
iso-butylcarbonylaminomethoxy, tert-butylcarbonylaminomethoxy,
2-(methylcarbonylamino)ethoxy, 2-(ethylcarbonylamino)ethoxy,
2-(n-propylcarbonylamino)ethoxy, 2-(iso-propylcarbohylamino)ethoxy,
2-(n-butylcarbonylamino)ethoxy, 2-(2-butylcarbonylamino)ethoxy,
2-(iso-butylcarbonylamino)ethoxy, 2-(tert-butylcarbonylamino)ethoxy.

[0135] C6-C12-Arylcarbonylamino-C1-C4-alkoxy is an
alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as
defined herein, wherein one hydrogen atom is replaced by a
C6-C12-arylcarbonylamino group as defined herein. Examples
include 2-(benzoylamino)ethoxy.

[0136] C1-C6-Alkoxycarbonylamino-C1-C4-alkoxy is an
alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as
defined herein, wherein one hydrogen atom is replaced by an
alkoxycarbonylamino group wherein the alkoxy group has from 1 to 6,
preferably from 1 to 4 carbon atoms as defined herein. Examples include
methoxycarbonylaminomethoxy, ethoxycarbonylaminomethoxy,
n-propoxycarbonylaminomethoxy, isopropoxycarbonylaminomethoxy,
n-butoxycarbonylaminomethoxy, 2-butoxycarbonylaminomethoxy,
iso-butoxycarbonylaminomethoxy, tert-butoxycarbonylaminomethoxy,
2-(methoxycarbonylamino)ethoxy, 2-(ethoxycarbonylamino)ethoxy,
2-(n-propoxycarbonylamino)ethoxy, 2-(iso-propoxycarbonylamino)ethoxy,
2-(n-butoxycarbonylamino)ethoxy, 2-(2-butoxycarbonylamino)ethoxy,
2-(isobutoxycarbonylamino)ethoxy, 2-(tert-butoxycarbonylamino)ethoxy.

[0137] C2-C6-Alkenyloxy is a radical of the formula R--O--,
wherein R is a straight-chain or branched alkenyl group having from 2 to
6, in particular 2 to 4 carbon atoms. Examples include vinyloxy, allyloxy
(2-propen-1-yloxy), 1-propen-1-yloxy, 2-propen-2-yloxy, methallyloxy
(2-methylprop-2-en-1-yloxy) and the like. C3-C5-Alkenyloxy is,
in particular, allyloxy, 1-methylprop-2-en-1-yloxy, 2-buten-1-yloxy,
3-buten-1-yloxy, methallyloxy, 2-penten-1-yloxy, 3-penten-1-yloxy,
4-penten-1-yloxy, 1-methylbut-2-en-1-yloxy or 2-ethylprop-2-en-1-yloxy.

[0138] C6-C12-Aryl-C1-C4-alkoxy is an alkoxy radical
having from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,
wherein one hydrogen atom is replaced by a C6-C12-aryl group as
defined herein. Examples include benzyloxy.

[0139] C1-C6-Alkylsulfonylamino-C1-C4-alkoxy is an
alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as
defined herein, wherein one hydrogen atom is replaced by an
alkylsulfonylamino group having from 1 to 6, preferably from 1 to 4
carbon atoms as defined herein. Examples include
2-(methylsulfonylamino)ethoxy, 2-(ethylsulfonylamino)ethoxy,
2-[(2-methylpropyl)sulfonylamino]ethoxy.

[0140] (Halogenated
C1-C6-alkyl)sulfonylamino-C1-C4-alkoxy is an alkoxy
radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined
herein, wherein one hydrogen atom is replaced by an alkylsulfonylamino
group having from 1 to 6, preferably from 1 to 4 carbon atoms as defined
herein, wherein the alkyl group is halogenated. Examples include
2-(trifluoromethylsulfonylamino)ethoxy.

[0141] C6-C12-Arylsulfonylamino-C1-C4-alkoxy is an
alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms as
defined herein, wherein one hydrogen atom is replaced by a
C6-C12-arylsulfonylamino group as defined herein. Examples
include 2-(phenylsulfonylamino)ethoxy, 2-(naphthylsulfonylamino)ethoxy.

[0142] (C6-C12-Aryl-C1-C6-alkyl)sulfonylamino-C1--
C4-alkoxy is an alkoxy radical having from 1 to 4, preferably 1 or 2
carbon atoms as defined herein, wherein one hydrogen atom is replaced by
a (C6-C12-aryl-C1-C6-alkyl)sulfonylamino group,
preferably by a
(C6-C12-aryl-C1-C2-alkyl)sulfonylamino group.
Examples include 2-(benzylsulfonylamino)ethoxy.

[0143] C3-C12-Heterocyclylsulfonylamino-C1-C4-alkoxy
is an alkoxy radical having from 1 to 4, preferably 1 or 2 carbon atoms
as defined herein, wherein one hydrogen atom is replaced by a
C3-C12-heterocyclylsulfonylamino group as defined herein.
Examples include 2-(pyridin-3-yl-sulfonylamino)ethoxy.

[0144] C3-C12-Heterocyclyl-C1-C4-alkoxy is an alkoxy
radical having from 1 to 4, preferably 1 or 2 carbon atoms as defined
herein, wherein one hydrogen atom is replaced by a
C3-C12-heterocyclyl group as defined herein. Examples include
2-(N-pyrrolidinyl)ethoxy, 2-(N-morpholinyl)ethoxy and
2-(N-imidazolyl)ethoxy.

[0145] C1-C2-Alkylenedioxo is a radical of the formula
--O--R--O--, wherein R is a straight-chain or branched alkylene group
having from 1 or 2 carbon atoms as defined herein. Examples include
methylenedioxo.

[0146] C6-C12-Aryloxy is a radical of the formula R--O--,
wherein R is an aryl group having from 6 to 12, in particular 6 carbon
atoms as defined herein. Examples include phenoxy.

[0147] C3-C12-Heterocyclyloxy is a radical of the formula
R--O--, wherein R is a C3-C12-heterocyclyl group having from 3
to 12, in particular from 3 to 7 carbon atoms as defined herein. Examples
include pyridin-2-yloxy.

[0152] (Halogenated C1-C6-alkyl)sulfonyl is a
C1-C6-alkylsulfonyl as defined herein, wherein at least one,
e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4
or a corresponding number of identical or different halogen atoms.

[0153] C6-C12-Arylsulfonyl is a radical of the formula
R--S(O)2--, wherein R is an aryl radical having from 6 to 12 carbon
atoms as defined herein. Examples include phenylsulfonyl.

[0154] (C6-C12-Aryl-C1-C4-alkyl)sulfonyl is a radical
of the formula R--S(O)2--, wherein R is a
C6-C12-aryl-C1-C4-alkyl radical, in particular a
C6-C12-aryl-C1-C2-alkyl radical as defined herein.
Examples include benzylsulfonyl.

[0155] C3-C12-Heterocyclylsulfonyl is a radical of the formula
R--S(O)2--, wherein R is C3-C12-heterocyclyl as defined
herein.

[0156] Aminosulfonyl is NH2--S(O)2--.

[0157] C1-C6-Alkylaminosulfonyl is a radical of the formula
R--NH--S(O)2-- wherein R is an alkyl radical having from 1 to 6,
preferably from 1 to 4 carbon atoms as defined herein. Examples include
methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl,
isopropylaminosulfonyl, n-butylaminosulfonyl, 2-butylaminosulfonyl,
iso-butylaminosulfonyl, tert-butylaminosulfonyl.

[0158] Di-C1-C6-alkylaminosulfonyl is a radical of the formula
RR'N--S(O)2-- wherein R and R' are independently of each other an
alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms as
defined herein. Examples include dimethylaminosulfonyl,
diethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl.

[0159] C6-C12-Arylaminosulfonyl is a radical of the formula
R--NH--S(O)2-- wherein R is an aryl radical having from 6 to 12,
preferably 6 carbon atoms as defined herein.

[0160] Amino is NH2.

[0161] C1-C6-Alkylamino is a radical of the formula R--NH--
wherein R is an alkyl radical having from 1 to 6, in particular from 1 to
4 carbon atoms as defined herein. Examples include methylamino,
ethylamino, n-propylamino, iso-propylamino, n-butylamino, 2-butylamino,
iso-butylamino, tert-butylamino.

[0162] (Halogenated C1-C6-alkyl)amino is a
C1-C6-alkylamino as defined herein, wherein at least one, e.g.
1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4 or a
corresponding number of identical or different halogen atoms.

[0163] Di-C1-C6-alkylamino is a radical of the formula RR'N--
wherein R and R' are independently of each other an alkyl radical having
from 1 to 6, in particular from 1 to 4 carbon atoms as defined herein.
Examples include dimethylamino, diethylamino, N-methyl-N-ethylamino.

[0164] Di-(halogenated C1-C6-alkyl)amino is a
di-C1-C6-alkylamino as defined herein, wherein at least one,
e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2, 3, 4
or a corresponding number of identical or different halogen atoms.

[0165] C1-C6-Alkylcarbonylamino is a radical of the formula
R--C(O)--NH--, wherein R is an alkyl radical having from 1 to 6, in
particular from 1 to 4 carbon atoms as defined herein. Examples include
acetamido (methylcarbonylamino), propionamido, n-butyramido,
2-methylpropionamido (isopropylcarbonylamino), 2,2-dimethylpropionamido
and the like.

[0166] (Halogenated C1-C6-alkyl)carbonylamino is a
C1-C6-alkylcarbonylamino as defined herein, wherein at least
one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2,
3, 4 or a corresponding number of identical or different halogen atoms.

[0167] C6-C12-Arylcarbonylamino is a radical of the formula
R--C(O)--NH--, wherein R is an aryl radical having from 6 to 12 carbon
atoms as defined herein. Examples include phenylcarbonylamino.

[0168] C2-C6-Alkenylamino is a radical of the formula R--NH--,
wherein R is a straight-chain or branched alkenyl group having from 2 to
6, in particular 2 to 4 carbon atoms. Examples include vinylamino,
allylamino (2-propen-1-ylamino), 1-propen-1-ylamino, 2-propen-2-ylamino,
methallylamino (2-methylprop-2-en-1-ylamino) and the like.
C3-C5-Alkenylamino is, in particular, allylamino,
1-methylprop-2-en-1-ylamino, 2-buten-1-ylamino, 3-buten-1-ylamino,
methallylamino, 2-penten-1-ylamino, 3-penten-1-ylamino,
4-penten-1-ylamino, 1-methylbut-2-en-1-ylamino or
2-ethylprop-2-en-1-ylamino.

[0169] C1-C6-Alkylsulfonylamino is a radical of the formula
R--S(O)2--NH--, wherein R is an alkyl radical having from 1 to 6, in
particular from 1 to 4 carbon atoms as defined herein. Examples include
methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino,
isopropylsulfonylamino, n-butylsulfonylamino, 2-butylsulfonylamino,
iso-butylsulfonylamino, tert-butylsulfonylamino.

[0170] (Halogenated C1-C6 alkyl)sulfonylamino is a
C1-C6-alkylsulfonylamino as defined herein, wherein at least
one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by 1, 2,
3, 4 or a corresponding number of identical or different halogen atoms.

[0171] C6-C12-Arylsulfonylamino is a radical of the formula
R--S(O)2--NH--, wherein R is an aryl radical having from 6 to 12
carbon atoms as defined herein. Examples include phenylsulfonylamino.

[0172] Nitro is --NO2.

[0173] C3-C12-Heterocyclyl is a 3- to 12-membered heterocyclic
radical including a saturated heterocyclic radical, which generally has
3, 4, 5, 6, or 7 ring forming atoms (ring members), an unsaturated
non-aromatic heterocyclic radical, which generally has 5, 6 or 7 ring
forming atoms, and a heteroaromatic radical (hetaryl), which generally
has 5, 6 or 7 ring forming atoms. The heterocyclic radicals may be bound
via a carbon atom (C-bound) or a nitrogen atom (N-bound). Preferred
heterocyclic radicals comprise 1 nitrogen atom as ring member atom and
optionally 1, 2 or 3 further heteroatoms as ring members, which are
selected, independently of each other from O, S and N. Likewise preferred
heterocyclic radicals comprise 1 heteroatom as ring member, which is
selected from O, S and N, and optionally 1, 2 or 3 further nitrogen atoms
as ring members.

[0187] Heterocyclyl also includes bicyclic heterocycles, which comprise
one of the described 5- or 6-membered heterocyclic rings and a further
anellated, saturated or unsaturated or aromatic carbocycle, such as a
benzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a further
anellated 5- or 6-membered heterocyclic ring, this heterocyclic ring
being saturated or unsaturated or aromatic. These include quinolinyl,
isoquinolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuryl,
benzthienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl and
benzimidazolyl. Examples of 5- or 6-membered heteroaromatic compounds
comprising an anellated cycloalkenyl ring include dihydroindolyl,
dihydroindolizinyl, dihydroisoindolyl, dihydroquinolinyl,
dihydroisoquinolinyl, chromenyl and chromanyl.

[0188] C3-C12-Heteroarylene is a heteroaryl diradical. Examples
include pyrid-2,5-ylene and pyrid-2,4-ylene.

[0190] In said formula (I) or (II), there may be one or more than one
substituent R, R2 and/or R3. More particularly, there may be up
to 3 substituents R2, and up to 6 substituents R3. Preferably
there is one substituent R and 1, 2 or 3 substituents R2. Formula
(I) may thus be depicted as follows:

##STR00018##

wherein a is 1, 2 or 3, b is 1, 2, 3, 4, 5 or 6 and c is 1. If there is
more than one radical R2, these may be the same or different
radicals. If there is more than one radical R3, these may be the
same or different radicals.

[0191] A is a 5- or 6-membered ring which includes two carbon atoms from
the cyclopentane, cyclohexane or cycloheptane moiety to which A is fused.
A may be a homocyclic or heterocyclic ring. The ring may be saturated,
unsaturated non-aromatic or aromatic. According to a particular
embodiment, A is a benzene ring. As a heterocyclic ring, A may include 1,
2 or 3 heteroatoms as ring member atoms, which are selected,
independently of each other from N, S and O. Preferred heterocyclic rings
comprise 1 nitrogen atom as ring member atom and optionally 1 or 2
further heteroatoms as ring members, which are selected, independently of
each other from O, S and N. Likewise preferred heterocyclic rings
comprise 1 heteroatom as ring member atom, which is selected from O, S
and N, and optionally 1 or 2 further nitrogen atoms as ring member atoms.
According to a particular embodiment, A is a heterocyclic ring selected
from the group consisting of the following 5- or 6-membered heterocyclic
rings:

##STR00019##

[0192] In said formulae, hydrogen atoms are not depicted. This is meant to
illustrate that the free valency of a carbon or nitrogen atom may be
either bound to a hydrogen atom, to R or to R2. Accordingly, R and
R2 may be C- or N-bound at any position of ring A.

[0193] The skilled person will appreciate that some of the rings depicted
above may be represented with a different structure, e.g. with hydrogen
atoms having other positions than those shown above, for instance as
given in the following structures:

##STR00020##

[0194] Preferably, A is a heterocyclic ring selected from the group
consisting of the following 5- or 6-membered heterocyclic rings:

##STR00021##

[0195] According to a further particular embodiment, A is a heterocyclic
ring selected from the group consisting of the following 5- or 6-membered
heterocyclic rings:

##STR00022##

[0196] According to a preferred embodiment, A is a heterocyclic ring
selected from the group consisting of the following 5- or 6-membered
heterocyclic rings:

##STR00023##

[0197] If ring A is a 5-membered heterocyclic ring it is preferred that R
is bound to G1 or G2, in particular G2:

##STR00024##

[0198] In said formula, G1, G2 and G3 independently are
--CH═, --CH2--, --N═, --NH--, S or O, at least one of
G1, G2 and G3 is --CH═ or --CH2--, the dotted
line represents a single or a double bond and R3, Y1, R4a,
R4b, X2, X3, R5, n are as defined herein.

[0199] If ring A is 6-membered heterocyclic ring it is preferred that R is
bound to G1 or G2, in particular G2:

##STR00025##

[0200] In said formula, G1, G2, G3 and G4
independently are --CH═, --CH2--, --N═, --NH--, S or O, at
least one of G1, G2, G3 and G4 is --CH═ or
--CH2--, the dotted line represents a single or a double bond and
R3, Y1, R4a, R4b, X2, X3, R5, n are as
defined herein.

[0201] Heterocyclic compounds having the following partial structures are
preferred:

##STR00026## ##STR00027##

[0202] Heterocyclic compounds having the following partial structures are
particularly preferred:

##STR00028##

[0203] In said formulae, R and R2 are as defined herein. If there is
more than one radical R2, these may be the same or different
radicals.

[0204] According to a particular embodiment, the partial structures
depicted above are fused with a cyclohexane moiety (i.e., n is 1). The
same applies to the preferred and particular embodiments disclosed for
ring A.

[0210] In connection with R1, substituted C6-C12-aryl in
particular includes C6-C12-aryl, such as phenyl or naphthyl,
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl,
cyano, C1-C4-alkoxy, C1-C4-haloalkoxy, amino,
C1-C4-alkylamino, C1-C4-dialkylamino, morpholino and
piperidinyl. The same applies to substituted C6-C12-aryl in
substituted C6-C12-aryl-C1-C4-alkyl.

[0211] In connection with R1, substituted
C3-C12-heterocyclyl in particular includes
C3-C12-heterocyclyl, such as pyridyl, thienyl, diazolyl,
quinolinyl, piperidinyl, piperazinyl or morpholinyl, pyrrolyl, isoxazolyl
and triazolyl being further examples of such
C3-C12-heterocyclyl, substituted with 1, 2 or 3 substituents
selected from the group consisting of halogen, C1-C4-alkyl,
C1-C4-haloalkyl, C1-C4-alkoxycarbonyl, cyano,
C1-C4-alkoxy, C1-C4-haloalkoxy,
C1-C4-alkylsulfonyl, amino, C1-C4-alkylamino,
C1-C4-dialkylamino, C6-C12-arylamino and
C3-C12-heterocyclyl (e.g., morpholino or piperidinyl). The same
applies to substituted C3-C12-heteroaryl in substituted
C3-C12-heteroaryl-C1-C4-alkyl.

[0212] According to one embodiment, W is --NR8-- and Y is a bond.
According to an alternative embodiment, W is a bond and Y is
--NR9--. According to a further alternative embodiment, W is a bond
and Y is a bond, especially if R1 is a nitrogen-bound radical, e.g.
nitrogen-bound heterocyclyl such as piperazinyl or morpholinyl.

[0213] According to one embodiment, Q is --S(O)2--. According to an
alternative embodiment, Q is --C(O)--.

[0214] According to a particular embodiment, --W-A1-Q-Y-- is
--W-A1-S(O)2--NR9--, --NR8--S(O)2--,
-A1-S(O)2-- or --S(O)2--. According to a further
particular embodiment, --W-A1-Q-Y-- is --W-A1-CO--NR9-- or
--NR8--CO--.

[0215] A1 is optionally substituted C1-C4-alkylene or a
bond. In connection with A1, substituted C1-C4-alkylene in
particular includes C1-C4-alkylene substituted with 1, 2 or 3
substituents selected from the group consisting of halogen,
C1-C4-alkyl and cyano. Preferably, A1 is a bond. If
A1 is C1-C4-alkylene, W is preferably --NRB--.

[0216] A2 is optionally substituted C1-C4-alkylene (e.g.
1,2-ethylene or 1,3-propylene), C1-C4-alkylene-CO--,
--CO--C1-C4-alkylene,
C1-C4-alkylene-O--C1-C4-alkylene,
C1-C4-alkylene-NR10--C1-C4-alkylene, optionally
substituted C6-C12-arylene, optionally substituted
C6-C12-heteroarylene or a bond. Additionally, A2 may be
optionally substituted C2-C4-alkenylene or optionally
substituted C2-C4-alkynylene. Preferably, A2 is optionally
substituted C1-C4-alkylene (e.g. 1,2-ethylene or
1,3-propylene). More preferably, A2 is C1-C4-alkylene
(e.g. 1,2-ethylene). Alternatively, it is preferred that A2 is
optionally substituted C6-C12-arylene, in particular
C6-C12-arylene selected from the group consisting of
phen-1,4-ylene and phen-1,3-ylene, or optionally substituted
C6-C12-heteroarylene, in particular
C6-C12-heteroarylene selected from the group consisting of
pyrid-2,5-ylene and pyrid-2,4-ylene. If A2 is a bond, X1 is
preferably optionally substituted C1-C4-alkylene.
Alternatively, if A2 is a bond, X1 is in particular optionally
substituted C2-C4-alkenylene or optionally substituted
C2-C4-alkynylene.

[0217] In connection with A2, substituted C1-C4-alkylene in
particular includes C1-C4-alkylene substituted with 1, 2 or 3
substituents selected from the group consisting of halogen,
C1-C4-alkyl, C1-C4-haloalkyl and cyano.

[0218] In connection with A2, substituted C2-C4-alkenylene
or substituted C2-C4-alkynylene in particular includes
C2-C4-alkenylene or C2-C4-alkynylene substituted with
1, 2 or 3 substituents selected from the group consisting of halogen,
C1-C4-alkyl, C1-C4-haloalkyl and cyano.

[0221] X1 is --O--, --NR11--, --S-- or optionally substituted
C1-C4-alkylene (e.g. --CH2--, 1,2-ethylene and
1,3-propylene). In connection with X1, substituted
C1-C4-alkylene in particular includes C1-C4-alkylene
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl
and cyano. Additionally, X1 may be optionally substituted
C2-C4-alkenylen or optionally substituted
C2-C4-alkynylene (e.g. propynylene). In connection with
X1, substituted C2-C4-alkenylene or substituted
C2-C4-alkynylene in particular includes
C2-C4-alkenylene or C2-C4-alkynylene substituted with
1, 2 or 3 substituents selected from the group consisting of halogen,
C1-C4-alkyl, C1-C4-haloalkyl and cyano. Preferably,
X1 is --O--, --NR11, --S--. More preferably, X1 is --O--.
Alternatively, it is preferred if X1 is optionally substituted
C1-C4-alkylene (e.g. --CH2-- or 1,2-ethylene).

[0222] According to a particular embodiment, A2 is a bond and X1
is optionally substituted C1-C4-alkylene, optionally
substituted C2-C4-alkenylene or optionally substituted
C2-C4-alkynylene.

[0223] According to a particular embodiment,
R1--W-A1-Q-Y-A2-X1-- is
R1--S(O)2--NH-A2-X1--,
R1--NH--S(O)2-A2-X1--,
R1--C(O)--NH-A2-X1- or R1--NH--C(O)-A2-X1-.

[0224] According to a particular embodiment, the structural element
--Y-A2-X1- comprises at least 2, 3 or 4 atoms in the main
chain. According to further particular embodiments the structural element
--Y-A2-X1- has up to 4, 5 or 6 atoms in the main chain, such as
2 to 6, 2 to 5 or 2 to 4 atoms in the main chain, especially 2, 3 or 4
atoms in the main chain.

[0225] According to a further particular embodiment, --Y-A2-X1--
is --C1-C4-alkylene-O-- or
--NR9--C1-C4-alkylene-O--, with --Y-A2-X1-
preferably having 2 to 6, 3 to 5 and especially 4 atoms in the main
chain. Particular examples of --Y-A2-X1- include
--(CH2)3--O-- and --NR9--(CH2)2--O--. In this
particular embodiment, R9 is as defined herein and preferably
R9 is hydrogen, C1-C6-alkyl (e.g. methyl or ethyl) or
C3-C12-cycloalkyl (e.g. cyclopropyl), or R9 is
C1-C4-alkylene that is bound to a carbon atom in A2 which
is C1-C4-alkylene.

[0226] According to a further particular embodiment, --Y-A2-X1-
is --NR9--C1-C4-alkylene- (e.g. --NH--CH2--,
--NH--(CH2)2-- or --NH--(CH2)3--), with
--Y-A2-X1- preferably having 2 to 6, 2 to 5, 2 to 4 and
especially 2, 3 or 4 atoms in the main chain. In this particular
embodiment, R9 is as defined herein and preferably R9 is
hydrogen, C1-C6-alkyl (e.g. methyl or ethyl) or
C3-C12-cycloalkyl (e.g. cyclopropyl); or R9 is
C1-C4-alkylene that is bound to a carbon atom in X1 which
is C1-C4-alkylene.

[0227] According to a further particular embodiment, --Y-A2-X1-
is --NR9--C2-C4-alkenylene- or
--NR9--C2-C4-alkynylene- (e.g.
--NH--CH2--C≡C--), with --Y-A2-X1- preferably having
2 to 6, 3 to 5 and especially 4 atoms in the main chain. In this
particular embodiment, R9 is as defined herein and preferably is
R9 is hydrogen, C1-C6-alkyl (e.g. methyl or ethyl) or
C3-C12-cycloalkyl (e.g. cyclopropyl or cyclobutyl). If A is a
heterocyclic ring, this embodiment of --Y-A2-X1- is
particularly suitable.

[0228] According to a further particular embodiment, --Y-A2-X1-
is --C1-C4-alkylene- (e.g. --(CH2)2--), with
--Y-A2-X1- preferably having 2 to 6, 2 to 5, 2 to 4 and
especially 2 atoms in the main chain. If A is a heterocyclic ring, this
embodiment of --Y-A2-X1- is particularly suitable.

[0229] According to a further particular embodiment, the structural motif
--Y-A2-X1 as disclosed herein is bound to Q being
--S(O)2-- or --C(O)--. Particular examples for this embodiment
include heterocyclic compounds of the invention wherein R is
R1--S(O)2--Y-A2-X1 or
R1--C(O)--Y-A2-X1.

[0230] The radical R and in particular the radical
R1--W-A1-Q-Y-A2-X1-- X1- may, in principle, be
bound to the 5-, 6-, 7- or 8-position of the skeleton of the compounds of
the invention:

[0232] Further particular examples include compounds of the above formulae
wherein the radical R1--W-A1-Q-Y-A2-X1-- is replaced
by the radical --CN.

[0233] Compounds of the invention having the radical
R1--W-A1-Q-Y-A2-X1- (or the radical --CN) in the 5-,
6-, 7-position are preferred.

[0234] Particularly preferred are compounds of the invention having the
radical R1--W-A1-Q-Y-A2-X1-- (or the radical --CN) in
the 7-position.

[0235] In addition to the radical R1--W-A1-Q-Y-A2-X1--
(or the radical --CN), the compounds of the invention may have one or
more than one further substituent bound to the ring A. In these
positions, the skeleton of the compounds of the invention may thus be
substituted with one or more than one radical R2. If there is more
than one radical R2, these may be the same or different radicals. In
particular, in 5-, 6-, 7- and/or 8-position, the skeleton of the
compounds of the invention may be substituted with one or more than one
radical R2. The compounds of the invention may therefore be
represented by one of the following formulae:

##STR00030##

or by corresponding formulae wherein the radical
R1--W-A1-Q-Y-A2-X1- is replaced by the radical --CN,
wherein R2a, R2b, R2c, R2d independently have one of
the meanings given for R2, and R1, W, A1, Q, Y, A2,
X1, R2, R3, Y1, R4a, R4b, X2, X3,
R5, n are as defined herein.

[0237] An optionally substituted 5- or 6-membered ring that is formed by
two radicals R2 together with the ring atoms of A to which they are
bound is, for instance, a benzene ring.

[0238] In connection with R2, substituted C6-C12-aryl in
particular includes C6-C12-aryl, such as phenyl, substituted
with 1, 2 or 3 substituents selected from the group consisting of halogen
and C1-C4-alkyl, C1-C4 haloalkyl, cyano,
C1-C4-alkoxy and C1-C4-haloalkoxy.

[0239] In connection with R2, substituted
C3-C12-heterocyclyl in particular includes
C3-C12-heterocyclyl, such as morpholinyl, pyrrolidinyl and
piperidinyl, substituted with 1, 2 or 3 substituents selected from the
group consisting of halogen, C1-C4-alkyl,
C1-C4-haloalkyl, cyano, C1-C4-alkoxy and
C1-C4-haloalkoxy.

[0242] In 1-, 2-, 3- and/or 4-position, the compounds of the invention may
be substituted with one or more than one radical R3. If there is
more than one radical R3, these may be the same or different
radicals. The compounds of the invention may therefore be represented by
the following formula:

[0244] R3 is hydrogen, halogen, C1-C6-alkyl,
C1-C6-alkoxy, or two radicals R3 together with the carbon
atom to which they are attached form a carbonyl group.

[0245] Preferably, R3 is hydrogen or C1-C6-alkyl. In
particular, R3 is hydrogen.

[0246] Y1 is optionally substituted C1-C4-alkylene (e.g.
methylene or 1,2-ethylene). In connection with Y1, substituted
C1-C4-alkylene in particular includes C1-C4-alkylene
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl,
C3-C12-cycloalkyl and cyano. In particular, Y1 is
C1-C4-alkylene (e.g. methylene or 1,2-ethylene).

[0250] Alternatively, R4a is optionally substituted
C1-C4-alkylene (e.g. methylene or 1,2-ethylene) that is bound
to a carbon atom in Y1. In connection with R4a, substituted
C1-C4-alkylene in particular includes C1-C4-alkylene
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl,
and cyano, with hydroxy and C1-C4-alkoxy being further
substituents. In particular, R4a is C1-C4-alkylene (e.g.
methylene or 1,2-ethylene) that is bound to a carbon atom in Y1 with
Y1 being optionally substituted C1-C4-alkylene (e.g.
1,2-ethylene or 1,3-propylene) so that R4a and at least part of
Y1 together with the nitrogen atom to which R4a and Y1 are
bound form an N-containing heterocyclic ring having, in particular, 4, 5
or 6 ring member atoms (including the nitrogen atom). An
alkylaminotetralin or indane derivative having such a ring may be
represented by the following partial structure:

[0253] Alternatively, R4a, R4b together are optionally
substituted C1-C6-alkylene (e.g. 1,4-butylene, 1,3-propylene,
2-fluoro-but-1,4-ylene or 1-oxo-but-1,4-ylene), wherein one --CH2--
of C1-C6-alkylene may be replaced by an oxygen atom (e.g.
--CH2--CH2--O--CH2--CH2--) or --NR16.

[0254] In connection with R4a and R4b, substituted
C1-C6-alkylene in particular includes C1-C6-alkylene
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen (e.g. fluoro or chloro), C1-C4-alkyl,
cyano, hydroxy and C1-C4-alkoxy.

[0260] In connection with R12a and R13a, substituted
C1-C6-alkyl in particular includes C1-C6-alkyl
substituted with 1, 2 or 3 substituents selected from the group
consisting of halogen, hydroxy, C1-C4-alkoxy and amino.

[0261] In connection with R12a and R13a, substituted
C6-C12-aryl in particular includes C6-C12-aryl, such
as phenyl, substituted with 1, 2 or 3 substituents selected from the
group consisting of C1-C4-alkyl, C1-C4-haloalkyl,
cyano, C1-C4-alkoxy and C1-C4-haloalkoxy.

[0262] R12b is hydrogen or C1-C6-alkyl. According to a
particular embodiment, R12b is hydrogen.

[0263] R13b is hydrogen or C1-C6-alkyl. According to a
particular embodiment, R13b is hydrogen.

[0264] Alternatively, R12a and R12b, or R13a and R13b,
together are together are carbonyl or, preferably, optionally substituted
C1-C4-alkylene (e.g. 1,3-propylene), wherein one --CH2--
of C1-C4-alkylene may be replaced by an oxygen atom or
--NR14--.

[0265] In connection with R12a and R12b, or R13a and
R13b, substituted C1-C4-alkylene in particular includes
C1-C4-alkylene substituted with 1, 2 or 3 substituents selected
from the group consisting of halogen, C1-C4-alkyl,
C1-C4-haloalkyl, cyano, C1-C4-alkoxy and
C1-C4-haloalkoxy.

[0266] According to a particular embodiment, R12a is
C1-C6-alkyl and R12b is hydrogen or C1-C6-alkyl,
or R13a is C1-C6-alkyl and R13b is hydrogen or
C1-C6-alkyl.

[0267] According to a further particular embodiment, R12a is hydrogen
and R12b is hydrogen, or R13a is hydrogen and R13b is
hydrogen.

[0268] According to a further particular embodiment, R12a and
R12b together are optionally substituted 1,3-propylene, or R13a
and R13b together are optionally substituted 1,3-propylene.

[0285] According to a particular embodiment, R9 and R1 together
are C1-C4-alkylene (e.g. 1, 3-1,2-ethylene or propylene) so as
that R9 and R1 together with the atom in Q to which R1 is
bound and the nitrogen atom to which R9 is bound form an
heterocyclic ring having, in particular, 4, 5 or 6 ring member atoms
(including the nitrogen atom and Q). With W and A1 both being a
bond, such a ring may be represented by the following partial structure:

[0286] According to a further particular embodiment, R9 is
C1-C4-alkylene (e.g. methylene or 1,3-propylene) that is bound
to a carbon atom in A2 and A2 is C1-C4-alkylene so
that R9 and at least part of A2 together with the nitrogen atom
to which R9 is bound form an N-containing heterocyclic ring having,
in particular, 4, 5, 6 or 7 ring member atoms (including the nitrogen
atom). Such a ring may be represented by the following partial structure:

##STR00039##

wherein W, A1, Q and X1 are as defined herein, p is 1 or 2, r
is 0, 1 or 2 and q is 0, 1 or 2. In this particular embodiment, X1
preferably is --O--. Particular combinations of p, r and q include p=1,
r=0, q=1; and p=1, r=0, q=0. Alternatively, p is 0, r is 3 and q is 1,
with X1 preferably being --O--.

[0287] According to a further particular embodiment, R9 is
C1-C4-alkylene (e.g. methylene or 1,3-propylene) that is bound
to a carbon atom in X1 and X1 is C1-C4-alkylene (e.g.
1,2-ethylene) so that R9 and at least part of X1 together with
the nitrogen atom to which R9 is bound form an N-containing
heterocyclic ring having, in particular, 4, 5, 6 or 7 ring member atoms
(including the nitrogen atom). With A2 being a bond, such a ring may
be represented by the following partial structure:

##STR00040##

wherein R1, W, A1 and Q are as defined herein, p is 1 or 2, r
is 0, 1 or 2 and q is 0, 1 or 2. Particular combinations of p, r and q
include p=1, r=0, q=0.

[0322] Further particular compounds of the present invention are the
individual derivatives (in particular tetraline and indane derivatives)
of the formula (Id) as listed in the following tables 1 to 24 and
physiologically tolerated salts thereof:

##STR00041##

[0323] Table 1

[0324] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is hydrogen, R3 is as defined herein and in particular
represents hydrogen, R17 is hydrogen and the combination of R1,
--Y-A2-X1--, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0325] Table 2

[0326] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is hydrogen, R3 is as defined herein and in particular
represents hydrogen, R17 is 3-F and the combination of R1,
--Y-A2-X1--, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0327] Table 3

[0328] Compounds of the formula (Id) wherein --Y1-- is as defined
herein and in particular represents --CH2-- or
--(--CH2)2--, R2 is hydrogen, R3 is as defined herein
and in particular represents hydrogen, R17 is 3-Cl and the
combination of R1, --Y-A2-X1--, >CR12aR12b,
R4a, R4b for a compound in each case corresponds to one line of
Table A (A-1 to A-480).

[0329] Table 4

[0330] Compounds of the formula (Id) wherein --Y1-- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is hydrogen, R3 is as defined herein and in particular
represents hydrogen, R17 is 3-CF3 and the combination of
R1, --Y-A2-X1--, >CR12aR12b, R4a,
R4b for a compound in each case corresponds to one line of Table A
(A-1 to A-480).

[0331] Table 5

[0332] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is hydrogen, R3 is as defined herein and in particular
represents hydrogen, R17 is 2-F and the combination of R1,
--Y-A2-X1--, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0333] Table 6

[0334] Compounds of the formula (Id) wherein --Y1-- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is hydrogen, R3 is as defined herein and in particular
represents hydrogen, R17 is 2-Cl and the combination of R1,
--Y-A2-X1--, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0335] Table 7

[0336] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 5-F, R3 is as defined herein and in particular represents
hydrogen, R17 is hydrogen and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0337] Table 8

[0338] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 5-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 3-F and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0339] Table 9

[0340] Compounds of the formula (Id) wherein --Y1-- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 5-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 3-Cl and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0341] Table 10

[0342] Compounds of the formula (Id) wherein --Y1-- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 5-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 3-CF3 and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0343] Table 11

[0344] Compounds of the formula (Id) wherein --Y1-- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 5-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 2-F and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0345] Table 12

[0346] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 5-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 2-Cl and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0347] Table 13

[0348] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 6-F, R3 is as defined herein and in particular represents
hydrogen, R17 is hydrogen and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0349] Table 14

[0350] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 6-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 3-F and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0351] Table 15

[0352] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 6-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 3-Cl and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0353] Table 16

[0354] Compounds of the formula (Id) wherein --Y1-- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 6-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 3-CF3 and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0355] Table 17

[0356] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 6-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 2-F and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0357] Table 18

[0358] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or (CH2)2--,
R2 is 6-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 2-Cl and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
for a compound in each case corresponds to one line of Table A (A-1 to
A-480).

[0359] Table 19

[0360] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 8-F, R3 is as defined herein and in particular represents
hydrogen, R17 is hydrogen and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0361] Table 20

[0362] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 8-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 3-F and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0363] Table 21

[0364] Compounds of the formula (Id) wherein --Y1-- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 8-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 3-Cl and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0365] Table 22

[0366] Compounds of the formula (Id) wherein --Y1-- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 8-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 3-CF3 and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0367] Table 23

[0368] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 8-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 2-F and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0369] Table 24

[0370] Compounds of the formula (Id) wherein --Y1- is as defined
herein and in particular represents --CH2-- or --(CH2)2--,
R2 is 8-F, R3 is as defined herein and in particular represents
hydrogen, R17 is 2-Cl and the combination of R1,
--Y-A2-X1-, >CR12aR12b, R4a, R4b for a
compound in each case corresponds to one line of Table A (A-1 to A-480).

[0371] Further particular compounds of the present invention are the
individual derivatives (in particular tetraline and indane derivatives)
of the formula (Id) as listed in the following tables 25 to 48 and
physiologically tolerated salts thereof:

##STR01018##

[0372] Table 25

[0373] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is hydrogen, R3 is as defined
herein and in particular represents hydrogen, R17 is hydrogen and
the combination of R1, --Y-A2-X1-,
>CR12aR12b, R4b for a compound in each case corresponds
to one line of Table A (A-481 to A-640).

[0374] Table 26

[0375] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is hydrogen, R3 is as defined
herein and in particular represents hydrogen, R17 is 3-F and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0376] Table 27

[0377] Compounds of the formula (Id) wherein --Y1NR4aR4b is
as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4-, R2 is hydrogen, R3 is as defined
herein and in particular represents hydrogen, R17 is 3-Cl and the
combination of R1, --Y-A2-X1--, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-1 to A-512).

[0378] Table 28

[0379] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is hydrogen, R3 is as defined
herein and in particular represents hydrogen, R17 is 3-CF3 and
the combination of R1, --Y-A2--X1-,
>CR12aR12b, R4b for a compound in each case corresponds
to one line of Table A (A-481 to A-640).

[0380] Table 29

[0381] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is hydrogen, R3 is as defined
herein and in particular represents hydrogen, R17 is 2-F and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0382] Table 30

[0383] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is hydrogen, R3 is as defined
herein and in particular represents hydrogen, R17 is 2-Cl and the
combination of R1, --Y-A2--X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0384] Table 31

[0385] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 5-F, R3 is as defined herein
and in particular represents hydrogen, R17 is hydrogen and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0386] Table 32

[0387] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 5-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 3-F and the
combination of R1, --Y-A2-X1--, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0388] Table 33

[0389] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 5-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 3-Cl and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0390] Table 34

[0391] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 5-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 3-CF3 and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0392] Table 35

[0393] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 5-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 2-F and the
combination of R1, --Y-A2-X1--, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0394] Table 36

[0395] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 5-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 2-Cl and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0396] Table 37

[0397] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 6-F, R3 is as defined herein
and in particular represents hydrogen, R17 is hydrogen and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0398] Table 38

[0399] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 6-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 3-F and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0400] Table 39

[0401] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 6-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 3-Cl and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0402] Table 40

[0403] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 6-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 3-CF3 and the
combination of R1, --Y-A2-X1--, >CR12aR12b,
R4a, R4b for a compound in each case corresponds to one line of
Table A (A-481 to A-640).

[0404] Table 41

[0405] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 6-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 2-F and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0406] Table 42

[0407] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 6-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 2-Cl and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0408] Table 43

[0409] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 8-F, R3 is as defined herein
and in particular represents hydrogen, R17 is hydrogen and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0410] Table 44

[0411] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 8-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 3-F and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4a, R4b for a compound in each case corresponds to one line of
Table A (A-481 to A-640).

[0412] Table 45

[0413] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 8-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 3-Cl and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0414] Table 46

[0415] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 8-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 3-CF3 and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0416] Table 47

[0417] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 8-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 2-F and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0418] Table 48

[0419] Compounds of the formula (Id) wherein --Y1--NR4aR4b
is as defined herein and in particular represents one of the partial
structures P1, P2, P3 or P4, R2 is 8-F, R3 is as defined herein
and in particular represents hydrogen, R17 is 2-Cl and the
combination of R1, --Y-A2-X1-, >CR12aR12b,
R4b for a compound in each case corresponds to one line of Table A
(A-481 to A-640).

[0421] Still further particular compounds of the present invention are the
compounds disclosed in preparation examples and physiologically tolerated
salts thereof. These include for each preparation example the exemplified
compound as well as the corresponding free base and any other
physiologically tolerated salts of the free base (if the exemplified
compound is a salt), or any physiologically tolerated salt of the free
base (if the exemplified compound is a free base). These further include
enantiomers, diastereomers, tautomers and any other isomeric forms of
said compounds, be they explicitly or implicitly disclosed.

[0422] The compounds of the formula (I) can be prepared by analogy to
methods which are well known in the art. Suitable methods for the
preparation of compounds of formula (I) are outlined in the following
schemes.

##STR01295##

[0423] As shown in scheme 1, the compound of general formula I readily
undergoes enamine alkylation to give the compound of general formula 3.

[0424] In scheme 1, the variables X1, R2, X2, X3,
R5 are as defined herein and L is a suitable protecting group (e.g.
L=Me). The process depicted in scheme 1 is also useful for obtaining
tetralines, wherein X1 is optionally substituted alkylene or oxygen.
In this case, L is a group that represents, or can be converted into, the
desired side chain R1--W-A1-Q-Y-A2-.

[0425] Alternatively, compounds of formula 3 can be prepared as described
in scheme 2.

[0427] In scheme 2a, the variables X1, R2, X2, X3,
R5 are as defined herein and L, 12 are a suitable protecting group
(e.g. L, L1=Me). Compounds 3 can be further converted to compounds
of the general formula (I).

##STR01297##

[0428] Scheme 2b depicts the general synthesis of indanones 3 using
transition metal-catalyzed C,C-bond formation to synthesize the indanone
from a diazoprecursor (cf. Tetrahedron Letters (2009), 50, 3568). Lx
is an ester moiety. The side chain containing X2, X3 and
R5 could be introduced by an alkylation of the 1,3-dicarbonyl
intermediate. Saponification of the ester moiety and decarboxylation
could yield indanone 3.

[0429] In scheme 2b, the variables X1, R2, X2, X3,
R3, R5 are as defined herein and L is a suitable protecting
group (e.g. L=Me). Compounds 3 can be further converted to compounds of
the general formula (I).

##STR01298## ##STR01299##

[0430] In scheme 2c, an alternative route to compounds 14 where n=0 is
depicted. A substituted 1-indanone can be functionalized in the
2-position after deprotonation next to the carbonyl followed by
alkylation with an electrophile bearing a protected nitrogen
(PG=protective group; this includes N(PG)2 being nitro and the
adjacent carbon in Y1 and N(PG)2 being nitrile). Addition of a
functionalized nucleophile (e.g. Li-organyl or Grignard reagent) to the
carbonyl of the 1-indanone followed by elimination and hydrogenation can
yield compound 8. Standard protective group chemistry followed by
alkylation, deprotection of the amine attached to A2 and reaction
with a substituted sulfonyl chloride can yield intermediate 12.

[0431] When N(PG)2 is a nitro group or when N(PG)2 and the
carbon in Y1 adjacent to N(PG)2 form a nitrile group the
activated C--H bond next to the nitro or nitrile can be used for
alkylation reactions with suitably functionalized electrophiles to yield
compounds 14 in which R4a is an optionally substituted alkylene that
is bound to a carbon atom in Y1. Alternatively the nitrogen attached
to Y1 in compound 12 can be deprotected and substituted to yield
compound 14.

[0433] The process depicted in scheme 3 is useful for obtaining tetralines
and indanes, wherein X1 is --O-- or --S--, A2 is optionally
substituted alkylene, Y is --NR9--, and Q is --S(O)2. Y1
is optionally substituted methylene or ethylene.

[0435] Compounds 7 in which Y1 is ethylene can be obtained from
compounds 3 in analogy to the protocol described in Helv. Chim. Acta
(1989), 72, 1463-70 or J. Med. Chem. (2000), 43, 4051-62 followed by
reduction of the corresponding nitrile (e.g. with lithium aluminum
hydride or borane tetrahydrofuran complex in tetrahydrofuran).

[0436] Compounds 7 in which Y1 is methylene can be obtained from
compounds 3 by Henry reaction in analogy to the protocol described in
DE3901814 followed by reduction of the corresponding nitro group (e.g.
catalytic hydrogenation with palladium on charcoal). Alternatively
compounds 7 in which Y1 is methylene can be obtained from compounds
3 in analogy to the protocol described in J. Med. Chem. (2000), 43,
4051-62 followed by Curtius rearrangement of the corresponding carboxylic
acid to the amine 7.

[0437] Side chains containing R1, W, A1, A2, X1 and
R9 and R5, X2 and X3 as well as the substituents
R2, R3, R4a and R4b can be introduced analog to the
protocols described in WO2009121872.

[0438] The process depicted in scheme 3a is useful for obtaining
tetralines, wherein X1 is --O-- or --S--, and Y is a bond.

[0440] Further protocols for the synthesis of compounds in which Y is a
bond and W is NR8 are described in WO 2009/121872.

##STR01302##

[0441] In scheme 3b, an alternative route to compound 9 is depicted.
Starting from a functionalized beta-keto ester the hydroxymethyl
intermediate can be obtained in analogy to the protocols described in
Bioorg. Med. Chem. Lett. 2005, 15, 1375. Compound 8 wherein Y1 is a
linker containing one carbon atom can be obtained in analogy to the
protocols described in Bioorg. Med. Chem. Lett. 2005, 15, 1375. To obtain
longer linkers Y1 with two or three carbon atoms the hydroxyl group
in the hydroxymethyl intermediate can either be converted to a leaving
group which then can be substituted by a cyanide or the hydroxymethyl
intermediate can be oxidized to an aldehyde which can be converted in a
Henry reaction to the corresponding nitro compound. Reduction (e.g.
hydrogenation) of the above nitriles or nitro compounds followed by
protection of the corresponding amine can give the compounds 9.

##STR01303##

[0442] In scheme 3c, an alternative route to the hydroxymethyl
intermediate described above is depicted. Analog to the protocols
described in Journal of Organic Chemistry (1981), 46(26), 5371, U.S. Pat.
No. 4,927,838 or
http://www3.interscience.wiley.com/cgi-bin/mrwhome/107610747/HOME the
aldehyde can be obtained which upon reduction (e.g. hydrogenation) can
yield the hydroxymethyl intermediate.

[0443] The process depicted in scheme 4 is useful for obtaining tetralines
and indanes, wherein X1 is methylene, A2 is a bond, Y is
--NR9--, and Q is --S(O)2.

##STR01304## ##STR01305##

[0444] Alternatively to triflate 19, the corresponding bromide or iodide
can be used to prepare compound 20.

[0446] Compounds 16 with Y1 methylene or ethylene can be obtained
from compound 15 in a similar fashion as compounds 7 from compounds 3.

[0447] Side chains containing R1, W, A1, X1 and R9 and
R5, X2 and X3 as well as the substituents R2,
R3, R4a and R4b can be introduced in analogy to the
protocols described in WO2009/121872.

[0448] The process depicted in scheme 5 is useful for obtaining tetralines
and indanes, wherein X1 is optionally substituted alkylene, A2
is optionally substituted alkylene or a bond, Y is --NR3--, and Q is
--S(O)2.

##STR01306##

[0449] Instead of the trifluoroborate 66, the corresponding
9-borabicyclo[3.3.1]non-9-yl derivative can be used to prepare compound
26.

[0451] The process depicted in scheme 6 is useful for obtaining tetralines
and indanes, wherein X is --NR11-, A2 is optionally substituted
alkylene, Y is --NR9--, and Q is --S(O)2. Y1 is optionally
substituted methylene or ethylene.

[0455] Compounds 8b and 17a can be obtained from compounds 3 and 15,
respectively, in analogy to the following protocols: J. Org. Chem.
(2006), 71, 7885-7887 and Organic Process Research & Development 2004, 8,
389-395.

[0457] The process depicted in the following schemes is useful for
obtaining compounds of the general formula (I) in which A is a
heterocycle.

##STR01314##

[0458] As shown in scheme 13, the compound of general formula 34 readily
undergoes condensation with dimethylformamide dimethyl acetal to give the
compound of general formula 35.

##STR01315##

[0459] As shown in the above scheme 8, the intermediate of general formula
35 reacts with various nucleophiles of general formula H2N--NH--R in
an alcoholic solvent preferably methanol or ethanol at a temperature of
about 20° to 80° C. to obtain the compounds of general
formulae 36 and 37. In case of monosubstituted hydrazines regioisomeric
products are formed. Compounds 36 and 37 can be transformed to compounds
of the general formula (I) as depicted in Scheme 15.

[0460] In schemes 14 the variable R is as defined herein.

##STR01316##

[0461] Alkylation of 38 can proceed via an enamine as described in scheme
1, or via an enolate. Compound 39 can be used in analogy to compound 3 to
prepare heterocyclic analogs of formula (I) depicted in Schemes 3 to 12.
In scheme 15, the variables R, R5, X2, X3 are as defined
herein.

##STR01317##

[0462] As shown in scheme 16, the reaction of compound of general formula
34 with hydroxyl(tosyloxy)iodobenzene gives the compound of formula 42.
Reaction of compound of general formula 42 with 1,3-nucleophiles under
appropriate conditions yield the compound of general formula 43. Compound
45 can be used in analogy to compound 3 to prepare heterocyclic analogs
of formula (I) depicted in Schemes 3 to 12. In scheme 16, the variables
R, R5, X2, X3 are as defined herein.

##STR01318##

[0463] As shown in scheme 17, the condensation of compound of general
formula 35 with reagent of general formula 49 and ammonia acetate in
refluxing acetic acid give compound of general formula 47, which can be
further transformed to compounds of general formula 48.

[0464] Compound 48 can be used in analogy to compound 3 to prepare
heterocyclic analogs of formula (I) depicted in Schemes 3 to 12. In
scheme 17, the variables R, R5, X2, X3 are as defined
herein.

##STR01319##

[0465] As shown in scheme 18, the cyclocondensation of intermediate of
general formula 35 with the 1,3-nucleophiles of general formula 50 in the
presence of suitable organic or inorganic bases such as KOH, NaOH,
NaHCO3, sodium ethoxide, sodium methoxide, triethyl amine and
diisopropyl ethyl amine in an alcoholic solvent, preferably ethanol or
methanol, at a temperature of about 20° to 80° C. yield the
compound of general formula 51, which can be transformed further to give
compounds of general formula 52. Compound 52 can be used in analogy to
compound 3 to prepare heterocyclic analogs of formula (I) depicted in
Schemes 3 to 12. In scheme 18, the variables R, R5, X2, X3
are as defined herein.

##STR01320##

[0466] As shown in scheme 19, the intermediate of general formula 53
readily can undergo condensation with dimethylformamide dimethyl acetal
to give the compound of general formula 54, which reacts with various
nucleophiles of general formula H2N--NH--R in an alcoholic solvent,
preferably methanol or ethanol, at a temperature of about 20° to
80° C. to afford the compound of general formula 55 and 56.
Compounds 57 and 58 can be used in analogy to compound 3 to prepare
heterocyclic analogs of formula (I) depicted in Schemes 3 to 12. In
scheme 19, the variables R, R5, X2, X3 are as defined
herein.

##STR01321##

[0467] As shown in scheme 20, the reaction of compound of general formula
53 with hydroxyl(tosyloxy)iodobenzene gives the compound of formula 59,
which reacts with 1,3-nucleophiles under appropriate conditions to yield
the compound of general formula 60. Further transformation results in
compounds of general formula 61. Compound 61 can be used analogous to
compound 3 to prepare heterocyclic analogs of formula (I) depicted in
Schemes 3 to 12. In scheme 20, the variables R, R5, X2, X3
are as defined herein.

##STR01322##

[0468] As shown in scheme 21, the cyclocondensation of intermediate of
general formula 54 with the 1,3-nucleophiles of general formula 50 in the
presence of suitable organic or inorganic bases such as KOH, NaOH,
NaHCO3, sodium ethoxide, sodium methoxide, triethyl amine and
diisopropyl ethyl amine in an alcoholic solvent, preferably ethanol or
methanol, at a temperature of about 20° to 80° C. yields
the compound of general formula 63, which can be transformed further to
give compounds of general formula 64. Compound 64 can be used in analogy
to compound 3 to prepare heterocyclic analogs of formula (I) depicted in
Schemes 3 to 12. In scheme 21, the variables R, R5, X2, X3
are as defined herein.

[0469] The acid addition salts of the compounds of formula (I) are
prepared in a customary manner by mixing the free base with a
corresponding acid, optionally in solution in an organic solvent, for
example a lower alcohol, such as methanol, ethanol or propanol, an ether,
such as methyl tert-butyl ether or diisopropyl ether, a ketone, such as
acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.

[0470] The compounds of formula (II)

##STR01323##

wherein L is an amino-protecting group, Y is NR9, and A2,
X1, A, R2, R3, Y1, R4a, R4b, X2,
X3, R5, n are defined as above are useful as intermediates in
the preparation of GlyT1 inhibitors, in particular those of formula (I).

[0473] The compounds of the formula (I) are capable of inhibiting the
activity of glycine transporter, in particular glycine transporter 1
(GlyT1).

[0474] The utility of the compounds in accordance with the present
invention as inhibiting the glycine transporter activity, in particular
GlyT1 activity, may be demonstrated by methodology known in the art. For
instance, human GlyT1c expressing recombinant hGlyT1c--5_CHO cells
can be used for measuring glycine uptake and its inhibition (IC50)
by a compound of formula (I).

[0475] Amongst the compounds of the formula (I) those are preferred which
achieve effective inhibition at low concentrations. In particular,
compounds of the formula (I) are preferred which inhibit glycine
transporter 1 (GlyT1) at a level of IC50<1 μMol, more
preferably at a level of IC50<0.5 μMol, particularly
preferably at a level of IC50<0.2 μMol and most preferably at
a level of IC50<0.1 μMol.

[0476] The compounds of the formula (I) according to the present invention
are thus useful as pharmaceuticals.

[0477] The present invention therefore also relates to pharmaceutical
compositions which comprise an inert carrier and a compound of the
formula (I).

[0478] The present invention also relates to the use of the compounds of
the formula (I) in the manufacture of a medicament for inhibiting the
glycine transporter GlyT1, and to corresponding methods of inhibiting the
glycine transporter GlyT1.

[0479] The NMDA receptor is central to a wide range of CNS processes, and
its role in a variety of diseases in humans or other species has been
described. GlyT1 inhibitors slow the removal of glycine from the synapse,
causing the level of synaptic glycine to rise. This in turn increases the
occupancy of the glycine binding site on the NMDA receptor, which
increases activation of the NMDA receptor following glutamate release
from the presynaptic terminal. Glycine transport inhibitors and in
particular inhibitors of the glycine transporter GlyT1 are thus known to
be useful in treating a variety of neurologic and psychiatric disorders.
Further, glycine A receptors play a role in a variety of diseases in
humans or other species. Increasing extracellular glycine concentrations
by inhibiting glycine trans-port may enhance the activity of glycine A
receptors. Glycine transport inhibitors and in particular inhibitors of
the glycine transporter GlyT1 are thus useful in treating a variety of
neurologic and psychiatric disorders.

[0480] The present invention thus further relates to the use of the
compounds of the formula (I) for the manufacture of a medicament for
treating a neurologic or psychiatric disorder, and to corresponding
methods of treating said disorders.

[0481] According to a particular embodiment, the disorder is associated
with glycinergic or glutamatergic neurotransmission dysfunction.

[0483] According to a further particular embodiment, the disorder is pain,
in particular chronic pain and especially neuropathic pain.

[0484] Pain can be classified as acute and chronic pain. Acute pain and
chronic pain differ in their etiology, pathophysiology, diagnosis and
treatment.

[0485] Acute pain, which occurs following tissue injury, is self-limiting,
serves as an alert to ongoing tissue damage and following tissue repair
it will usually subside. There are minimal psychological symptoms
associated with acute pain apart from mild anxiety. Acute pain is
nociceptive in nature and occurs following chemical, mechanical and
thermal stimulation of A-delta and C-polymodal pain receptors.

[0486] Chronic pain, on the other hand, serves no protective biological
function. Rather than being the symptom of tissue damage it is a disease
in its own right. Chronic pain is unrelenting and not self-limiting and
can persist for years, perhaps decades after the initial injury. Chronic
pain can be refractory to multiple treatment regimes. Psychological
symptoms associated with chronic pain include chronic anxiety, fear,
depression, sleeplessness and impairment of social interaction. Chronic
non-malignant pain is predominantly neuropathic in nature and involves
damage to either the peripheral or central nervous systems.

[0487] Acute pain and chronic pain are caused by different
neuro-physiological processes and therefore tend to respond to different
types of treatments. Acute pain can be somatic or visceral in nature.
Somatic pain tends to be a well localised, constant pain and is described
as sharp, aching, throbbing or gnawing. Visceral pain, on the other hand,
tends to be vague in distribution, paroxysmal in nature and is usually
described as deep, aching, squeezing or colicky in nature. Examples of
acute pain include post-operative pain, pain associated with trauma and
the pain of arthritis. Acute pain usually responds to treatment with
opioids or non-steroidal anti-inflammatory drugs.

[0488] Chronic pain, in contrast to acute pain, is described as burning,
electric, tingling and shooting in nature. It can be continuous or
paroxysmal in presentation. The hallmarks of chronic pain are chronic
allodynia and hyperalgesia. Allodynia is pain resulting from a stimulus
that normally does not elicit a painful response, such as a light touch.
Hyperalgesia is an increased sensitivity to normally painful stimuli.
Primary hyperalgesia occurs immediately within the area of the injury.
Secondary hyperalgesia occurs in the undamaged area surrounding the
injury. Examples of chronic pain include complex regional pain syndrome,
pain arising from peripheral neuropathies, post-operative pain, chronic
fatigue syndrome pain, tension-type headache, pain arising from
mechanical nerve injury and severe pain associated with diseases such as
cancer, metabolic disease, neurotropic viral disease, neurotoxicity,
inflammation, multiple sclerosis or any pain arising as a consequence of
or associated with stress or depressive illness.

[0489] Although opioids are cheap and effective, serious and potentially
life-threatening side effects occur with their use, most notably
respiratory depression and muscle rigidity. In addition the doses of
opioids which can be administered are limited by nausea, emesis,
constipation, pruritis and urinary retention, often resulting in patients
electing to receive suboptimal pain control rather than suffer these
distressing side-effects. Furthermore, these side-effects often result in
patients requiring extended hospitalization. Opioids are highly addictive
and are scheduled drugs in many territories.

[0494] Particular neurologic disorders that can be treated with the
compounds of the formula (I) include in particular a cognitive disorder
such as dementia, cognitive impairment, attention deficit hyperactivity
disorder.

[0495] Particular psychiatric disorders that can be treated with the
compounds of the formula (I) include in particular an anxiety disorder, a
mood disorder such as depression or a bipolar disorder, schizophrenia, a
psychotic disorder.

[0496] Within the context of the treatment, the use according to the
invention of the compounds of the formula (I) involves a method. In this
method, an effective quantity of one or more compounds or the formula
(I), as a rule formulated in accordance with pharmaceutical and
veterinary practice, is administered to the individual to be treated,
preferably a mammal, in particular a human being. Whether such a
treatment is indicated, and in which form it is to take place, depends on
the individual case and is subject to medical assessment (diagnosis)
which takes into consideration signs, symptoms and/or malfunctions which
are present, the risks of developing particular signs, symptoms and/or
malfunctions, and other factors.

[0497] As a rule, the treatment is effected by means of single or repeated
daily administration, where appropriate together, or alternating, with
other drugs or drug-containing preparations.

[0498] The invention also relates to the manufacture of pharmaceutical
compositions for treating an individual, preferably a mammal, in
particular a human being. Thus, the compounds of the formula (I) are
customarily administered in the form of pharmaceutical compositions which
comprise an inert carrier (e.g. a pharmaceutically acceptable excipient)
together with at least one compound according to the invention and, where
appropriate, other drugs. These compositions can, for example, be
administered orally, rectally, transdermally, subcutaneously,
intravenously, intramuscularly or intranasally.

[0499] Examples of suitable pharmaceutical formulations are solid
medicinal forms, such as powders, granules, tablets, in particular film
tablets, lozenges, sachets, cachets, sugar-coated tablets, capsules, such
as hard gelatin capsules and soft gelatin capsules, suppositories or
vaginal medicinal forms, semisolid medicinal forms, such as ointments,
creams, hydrogels, pastes or plasters, and also liquid medicinal forms,
such as solutions, emulsions, in particular oil-in-water emulsions,
suspensions, for example lotions, injection preparations and infusion
preparations, and eyedrops and eardrops. Implanted release devices can
also be used for administering inhibitors according to the invention. In
addition, it is also possible to use liposomes or microspheres.

[0500] When producing the compositions, the compounds according to the
invention are optionally mixed or diluted with one or more carriers
(excipients). Carriers (excipients) can be solid, semisolid or liquid
materials which serve as vehicles, carriers or medium for the active
compound.

[0502] The compounds of formula (I) may also be suitable for combination
with other therapeutic agents.

[0503] Thus, the present invention also provides:

i) a combination comprising a compound of formula (I) with one or more
further therapeutic agents; ii) a pharmaceutical composition comprising a
combination product as defined in i) above and at least one carrier,
diluent or excipient; iii) the use of a combination as defined in i)
above in the manufacture of a medicament for treating or preventing a
disorder, disease or condition as defined herein; iv) a combination as
defined in i) above for use in treating or preventing a disorder, disease
or condition as defined herein; v) a kit-of-parts for use in the
treatment of a disorder, disease or condition as defined herein,
comprising a first dosage form comprising a compound of formula (I) and
one or more further dosage forms each comprising one or more further
therapeutic agents for simultaneous therapeutic administration, vi) a
combination as defined in i) above for use in therapy; vii) a method of
treatment or prevention of a disorder, disease or condition as defined
herein comprising administering an effective amount of a combination as
defined in i) above; viii) a combination as defined in i) above for
treating or preventing a disorder, disease or condition as defined
herein.

[0504] The combination therapies of the invention may be administered
adjunctively. By adjunctive administration is meant the coterminous or
overlapping administration of each of the components in the form of
separate pharmaceutical compositions or devices. This regime of
therapeutic administration of two or more therapeutic agents is referred
to generally by those skilled in the art and herein as adjunctive
therapeutic administration; it is also known as add-on therapeutic
administration. Any and all treatment regimes in which a patient receives
separate but coterminous or overlapping therapeutic administration of the
compounds of formula (I) and at least one further therapeutic agent are
within the scope of the current invention. In one embodiment of
adjunctive therapeutic administration as described herein, a patient is
typically stabilised on a therapeutic administration of one or more of
the components for a period of time and then receives administration of
another component.

[0505] The combination therapies of the invention may also be administered
simultaneously. By simultaneous administration is meant a treatment
regime wherein the individual components are administered together,
either in the form of a single pharmaceutical composition or device
comprising or containing both components, or as separate compositions or
devices, each comprising one of the components, administered
simultaneously. Such combinations of the separate individual components
for simultaneous combination may be provided in the form of a
kit-of-parts.

[0506] In a further aspect, the invention provides a method of treatment
of a psychotic disorder by adjunctive therapeutic administration of
compounds of formula (I) to a patient receiving therapeutic
administration of at least one antipsychotic agent. In a further aspect,
the invention provides the use of compounds of formula (I) in the
manufacture of a medicament for adjunctive therapeutic administration for
the treatment of a psychotic disorder in a patient receiving therapeutic
administration of at least one antipsychotic agent. The invention further
provides compounds of formula (I) for use for adjunctive therapeutic
administration for the treatment of a psychotic disorder in a patient
receiving therapeutic administration of at least one antipsychotic agent.

[0507] In a further aspect, the invention provides a method of treatment
of a psychotic disorder by adjunctive therapeutic administration of at
least one antipsychotic agent to a patient receiving therapeutic
administration of compounds of formula (I). In a further aspect, the
invention provides the use of at least one antipsychotic agent in the
manufacture of a medicament for adjunctive therapeutic administration for
the treatment of a psychotic disorder in a patient receiving therapeutic
administration of compounds of formula (I). The invention further
provides at least one antipsychotic agent for adjunctive therapeutic
administration for the treatment of a psychotic disorder in a patient
receiving therapeutic administration of compounds of formula (I).

[0508] In a further aspect, the invention provides a method of treatment
of a psychotic disorder by simultaneous therapeutic administration of
compounds of formula (I) in combination with at least one antipsychotic
agent. The invention further provides the use of a combination of
compounds of formula (I) and at least one antipsychotic agent in the
manufacture of a medicament for simultaneous therapeutic administration
in the treatment of a psychotic disorder. The invention further provides
a combination of compounds of formula (I) and at least one antipsychotic
agent for simultaneous therapeutic administration in the treatment of a
psychotic disorder. The invention further provides the use of compounds
of formula (I) in the manufacture of a medicament for simultaneous
therapeutic administration with at least one antipsychotic agent in the
treatment of a psychotic disorder. The invention further provides
compounds of formula (I) for use for simultaneous therapeutic
administration with at least one antipsychotic agent in the treatment of
a psychotic disorder. The invention further provides the use of at least
one antipsychotic agent in the manufacture of a medicament for
simultaneous therapeutic administration with compounds of formula (I) in
the treatment of a psychotic disorder. The invention further provides at
least one antipsychotic agent for simultaneous therapeutic administration
with compounds of formula (I) in the treatment of a psychotic disorder.

[0509] In further aspects, the invention provides a method of treatment of
a psychotic disorder by simultaneous therapeutic administration of a
pharmaceutical composition comprising compounds of formula (I) and at
least one mood stabilising or antimanic agent, a pharmaceutical
composition comprising compounds of formula (I) and at least one mood
stabilising or antimanic agent, the use of a pharmaceutical composition
comprising compounds of formula (I) and at least one mood stabilising or
antimanic agent in the manufacture of a medicament for the treatment of a
psychotic disorder, and a pharmaceutical composition comprising compounds
of formula (I) and at least one mood stabilising or antimanic agent for
use in the treatment of a psychotic disorder.

[0510] Antipsychotic agents include both typical and atypical
antipsychotic drugs. Examples of antipsychotic drugs that are useful in
the present invention include, but are not limited to: butyrophenones,
such as haloperidol, pimozide, and droperidol; phenothiazines, such as
chlorpromazine, thioridazine, mesoridazine, trifluoperazine,
perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and
acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene;
thienobenzodiazepines; dibenzodiazepines; benzisoxazoles;
dibenzothiazepines; imidazolidinones; benziso- thiazolyl-piperazines;
triazine such as lamotrigine; dibenzoxazepines, such as loxapine;
dihydroindolones, such as molindone; aripiprazole; and derivatives
thereof that have antipsychotic activity.

[0511] Examples of tradenames and suppliers of selected antipsychotic
drugs are as follows: clozapine (available under the tradename
CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine
(available under the tradename ZYPREX®, from Lilly); ziprasidone
(available under the tradename GEODON®, from Pfizer); risperidone
(available under the tradename RISPERDAL®, from Janssen); quetiapine
fumarate (available under the tradename SEROQUEL®, from AstraZeneca);
haloperidol (available under the tradename HALDOL®, from
Ortho-McNeil); chlorpromazine (available under the tradename
THORAZINE®, from SmithKline Beecham (GSK)); fluphenazine (available
under the tradename PROLIXIN®, from Apothecon, Copley, Schering,
Teva, and American Pharmaceutical Partners, Pasadena); thiothixene
(available under the tradename NAVANE®, from Pfizer); trifluoperazine
(10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazine
dihydrochloride, available under the tradename STELAZINE®, from Smith
Klein Beckman); perphenazine (available under the tradename
TRILAFON®; from Schering); thioridazine (available under the
tradename MELLARIL®; from Novartis, Roxane, HiTech, Teva, and
Alpharma); molindone (available under the tradename MOBAN®, from
Endo); and loxapine (available under the tradename LOXITANE(D; from
Watson). Furthermore, benperidol (Glianimon®), perazine
(Taxilan®) or melperone (Eunerpan®) may be used. Other
antipsychotic drugs include promazine (available under the tradename
SPARINE®), triflurpromazine (available under the tradename VESPRI
N®), chlorprothixene (available under the tradename TARACTAN®),
droperidol (available under the tradename INAPSINE®), acetophenazine
(available under the tradename TINDAL®), prochlorperazine (available
under the tradename COMPAZINE®), methotrimeprazine (available under
the tradename NOZINAN®), pipotiazine (available under the tradename
PIPOTRIL®), ziprasidone, and hoperidone.

[0512] In a further aspect, the invention provides a method of treatment
of a neurodegenerative disorder such as Alzheimer Disease by adjunctive
therapeutic administration of compounds of formula (I) to a patient
receiving therapeutic administration of at least one agent suitable for
the treatment of a neurodegenerative disorder such as Alzheimer Disease.
In a further aspect, the invention provides the use of compounds of
formula (I) in the manufacture of a medicament for adjunctive therapeutic
administration for the treatment of a neurodegenerative disorder such as
Alzheimer Disease in a patient receiving therapeutic administration of at
least one agent suitable for the treatment of a neurodegenerative
disorder such as Alzheimer Disease. The invention further provides
compounds of formula (I) for use for adjunctive therapeutic
administration for the treatment of a neurodegenerative disorder such as
Alzheimer Disease in a patient receiving therapeutic administration of at
least one agent suitable for the treatment of a neurodegenerative
disorder such as Alzheimer Disease.

[0513] In a further aspect, the invention provides a method of treatment
of a neurodegenerative disorder such as Alzheimer Disease by adjunctive
therapeutic administration of at least one agent suitable for the
treatment of a neurodegenerative disorder such as Alzheimer Disease to a
patient receiving therapeutic administration of compounds of formula (I).
In a further aspect, the invention provides the use of at least one agent
suitable for the treatment of a neurodegenerative disorder such as
Alzheimer Disease in the manufacture of a medicament for adjunctive
therapeutic administration for the treatment of a neurodegenerative
disorder such as Alzheimer Disease in a patient receiving therapeutic
administration of compounds of formula (I). The invention further
provides at least one agent suitable for the treatment of a
neurodegenerative disorder such as Alzheimer Disease for adjunctive
therapeutic administration for the treatment of a neurodegenerative
disorder such as Alzheimer Disease in a patient receiving therapeutic
administration of compounds of formula (I).

[0514] In a further aspect, the invention provides a method of treatment
of a neurodegenerative disorder such as Alzheimer Disease by simultaneous
therapeutic administration of compounds of formula (I) in combination
with at least one agent suitable for the treatment of a neurodegenerative
disorder such as Alzheimer Disease. The invention further provides the
use of a combination of compounds of formula (I) and at least one agent
suitable for the treatment of a neurodegenerative disorder such as
Alzheimer Disease in the manufacture of a medicament for simultaneous
therapeutic administration in the treatment of a neurodegenerative
disorder such as Alzheimer Disease. The invention further provides a
combination of compounds of formula (I) and at least one agent suitable
for the treatment of a neurodegenerative disorder such as Alzheimer
Disease for simultaneous therapeutic administration in the treatment of a
neurodegenerative disorder such as Alzheimer Disease. The invention
further provides the use of compounds of formula (I) in the manufacture
of a medicament for simultaneous therapeutic administration with at least
one agent suitable for the treatment of a neurodegenerative disorder such
as Alzheimer Disease in the treatment of a neurodegenerative disorder
such as Alzheimer Disease. The invention further provides compounds of
formula (I) for use for simultaneous therapeutic administration with at
least one agent suitable for the treatment of a neurodegenerative
disorder such as Alzheimer Disease in the treatment of a
neurodegenerative disorder such as Alzheimer Disease. The invention
further provides the use of at least one agent suitable for the treatment
of a neurodegenerative disorder such as Alzheimer Disease in the
manufacture of a medicament for simultaneous therapeutic administration
with compounds of formula (I) in the treatment of a neurodegenerative
disorder such as Alzheimer Disease. The invention further provides at
least one agent suitable for the treatment of a neurodegenerative
disorder such as Alzheimer Disease for simultaneous therapeutic
administration with compounds of formula (I) in the treatment of a
neurodegenerative disorder such as Alzheimer Disease.

[0516] Suitable cholinesterase inhibitors which may be used in combination
with the compounds of the inventions include for example tacrine,
donepezil, galantamine and rivastigmine.

[0517] Suitable NMDA receptors targeting agents which may be used in
combination with the compounds of the inventions include for example
memantine.

[0518] Suitable agents affecting increased HPA axis activity which may be
used in combination with the compounds of the inventions include for
example CRF1 antagonists or V1b antagonists.

[0519] In a further aspect therefore, the invention provides a method of
treatment of pain by adjunctive therapeutic administration of compounds
of formula (I) to a patient receiving therapeutic administration of at
least one agent suitable for the treatment of pain. In a further aspect,
the invention provides the use of compounds of formula (I) in the
manufacture of a medicament for adjunctive therapeutic administration for
the treatment of pain in a patient receiving therapeutic administration
of at least one agent suitable for the treatment of pain. The invention
further provides compounds of formula (I) for use for adjunctive
therapeutic administration for the treatment of pain in a patient
receiving therapeutic administration of at least one agent suitable for
the treatment of pain.

[0520] In a further aspect, the invention provides a method of treatment
of pain by adjunctive therapeutic administration of at least one agent
suitable for the treatment of pain to a patient receiving therapeutic
administration of compounds of formula (I). In a further aspect, the
invention provides the use of at least one agent suitable for the
treatment of pain in the manufacture of a medicament for adjunctive
therapeutic administration for the treatment of pain in a patient
receiving therapeutic administration of compounds of formula (I).

[0521] The invention further provides at least one agent suitable for the
treatment of pain for adjunctive therapeutic administration for the
treatment of pain in a patient receiving therapeutic administration of
compounds of formula (I).

[0522] In a further aspect, the invention provides a method of treatment
of pain by simultaneous therapeutic administration of compounds of
formula (I) in combination with at least one agent suitable for the
treatment of pain. The invention further provides the use of a
combination of compounds of formula (I) and at least one agent suitable
for the treatment of pain in the manufacture of a medicament for
simultaneous therapeutic administration in the treatment of pain. The
invention further provides a combination of compounds of formula (I) and
at least one agent suitable for the treatment of pain for simultaneous
therapeutic administration in the treatment of pain. The invention
further provides the use of compounds of formula (I) in the manufacture
of a medicament for simultaneous therapeutic administration with at least
one agent suitable for the treatment of pain in the treatment of pain.
The invention further provides compounds of formula (I) for use for
simultaneous therapeutic administration with at least one agent suitable
for the treatment of pain in the treatment of pain. The invention further
provides the use of at least one agent suitable for the treatment of pain
in the manufacture of a medicament for simultaneous therapeutic
administration with compounds of formula (I) in the treatment of pain.
The invention further provides at least one agent suitable for the
treatment of pain for simultaneous therapeutic administration with
compounds of formula (I) in the treatment of pain.

[0523] Examples of agents suitable for the treatment of pain that are
useful in the present invention include, but are not limited to: NSAIDs
(Nonsteroidal Antiinflammatory Drugs), anti-convulsant drugs such as
carbamazepine and gabapentin, sodium channel blockers, anti-depressant
drugs, cannabinoids and local anesthetics.

[0525] It will be appreciated by those skilled in the art that the
compounds according to the invention may advantageously be used in
conjunction with one or more other therapeutic agents, for instance,
antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1
antagonists, selective serotonin reuptake inhibitors (SSRI),
noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants,
dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B
antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or
anticonvulsant agents, as well as cognitive enhancers.

[0526] Suitable 5HT3 antagonists which may be used in combination of the
compounds of the inventions include for example ondansetron, granisetron,
metoclopramide.

[0527] Suitable serotonin agonists which may be used in combination with
the compounds of the invention include sumatriptan, rauwolscine,
yohimbine, metoclopramide.

[0528] Suitable SSRIs which may be used in combination with the compounds
of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine,
paroxetine, indalpine, sertraline, zimeldine.

[0529] Suitable SNRIs which may be used in combination with the compounds
of the invention include venlafaxine and reboxetine.

[0530] Suitable tricyclic antidepressants which may be used in combination
with a compound of the invention include imipramine, amitriptiline,
chlomipramine and nortriptiline.

[0531] Suitable dopaminergic antidepressants which may be used in
combination with a compound of the invention include bupropion and
amineptine.

[0532] Suitable anticonvulsant agents which may be used in combination of
the compounds of the invention include for example divaiproex,
carbamazepine and diazepam.

[0533] The following examples serve to explain the invention without
limiting it.

[0534] The compounds were characterized by mass spectrometry, generally
recorded via HPLC-MS in a fast gradient on C18-material
(electrospray-ionisation (ESI) mode).

Preparation Examples

[0535] The following compounds were obtained or can be obtained using the
procedures described herein.

[0539] 1. [3H]-Glycine uptake into recombinant CHO cells expressing
human GlyT1: Human GlyT1c expressing recombinant hGlyT1c--5_CHO
cells were plated at 20,000 cells per well in 96 well Cytostar-T
scintillation microplates (Amersham Biosciences) and cultured to
sub-confluency for 24 h. For glycine uptake assays the culture medium was
aspirated and the cells were washed once with 100 μl HBSS (Gibco BRL,
#14025-050) with 5 mM L-Alanine (Merck #1007). 80 μl HBSS buffer were
added, followed by 10μl inhibitor or vehicle (10% DMSO) and 10 μl
[3H]-glycine (TRK71, Amersham Biosciences) to a final concentration
of 200 nM for initiation of glycine uptake. The plates were placed in a
Wallac Microbeta (PerkinElmer) and continuously counted by solid phase
scintillation spectrometry during up to 3 hours. Nonspecific uptake was
determined in the presence of 10 μM Org24598. IC50 calculations
were made by four-parametric logistic nonlinear regression analysis
(GraphPad Prism) using determinations within the range of linear increase
of [3H]-glycine incorporation between 60 and 120 min.